Total Synthesis of the Macroline-related Alkaloid ...Total Synthesis of the Macroline-related...

Total Synthesis of the Macroline-related Alkaloid

(±)-Alstonerine

Richard Pett

June 2013

Thorpe Laboratory 860, Department of Chemistry, Imperial College London, London, SW7 2AZ,

United Kingdom

A thesis submitted in partial fulfilment of the requirements for the degree of Doctor of

Philosophy, Imperial College London.

Abstract

This thesis examines the total synthesis of the macroline-related indole alkaloid alstonerine and

related compounds. It is divided into three sections:

The first section provides a review of the total synthesis efforts reported by Cook, Martin,

Kuethe, and Kwon, as well previous work within the Craig group.

The second section discusses the results of our investigations. The optimisation of the synthesis

of key intermediate α,β-unsaturated lactam alcohol via directed-aziridine ring-opening is

presented in detail. Our progress towards the synthesis of macroline-related alkaloids macroline,

alstolactone, anhydromacrosalhine-methine and alstonerinal, as well as their N4-tosyl derivatives,

from the key intermediate is discussed. The findings from these studies are presented en route to

the total synthesis of alstonerine.

The third section contains experimental procedures and characterisation data for compounds

synthesised.

Table of contents

Abstract 2

Table of contents 3

Copyright and Originality Declarations 5

Acknowledgements 6

List of abbreviations 8

Stereochemical notation 10

Chapter 1. Introduction 11

1.1 Introduction to macroline, sarpagine and ajmaline-related indole alkaloids 12

1.2 Cook’s approach to (–)-alstonerine and related compounds 15

1.3 Kuethe’s aza-Diels–Alder approach 25

1.4 Kwon’s phosphine-catalysed [4+2] annulation synthesis 27

1.5 Martin’s Pauson–Khand Synthesis 29

1.6 The Craig group’s previous approaches to alstonerine 33

Chapter 2. Results and Discussion 48

2.1 Synthesis of key intermediate α,β-unsaturated lactam alcohol 90 51

2.1.1 Synthesis of aziridine ring-opening reaction substrates 51

2.1.2 Synthesis of hydroxymethyl-substituted aziridine 82 51

2.1.3 Synthesis of sulfone 88 52

2.1.4 Recyrstallisation of sulfone 99 53

2.1.5 Optimisation of dichlorocyclopropanation synthesis of 98 54

2.1.6 Initial work towards the synthesis of key intermediate lactam–alcohol 90 57

2.1.7 Substrate stability and mechanistic investigation 58

2.1.8 Sulfone stability 59

2.1.9 Aziridine 82 reactivity towards sulfone nucleophiles 61

2.1.10 Orthoester hydrolysis in the synthesis of 102 62

2.1.11 O-TBS protected aziridine 96 ring-opening strategy 65

2.1.12 Deprotection of ring-opening product 102 67

2.1.13 Esterification of sulfonamidoalcohol 89 and TMA mediated cyclisation 69

2.1.14 Final synthesis of synthesis of α,β-unsaturated lactam–alcohol 90 72

2.2 Synthesis of Macroline-related alkaloids from lactam–alcohol 90 76

2.2.1 Synthesis of lactam–lactone 91 76

2.2.2 Synthesis of 85 via C-ring forming Pictet–Spengler cyclisation 78

2.2.3 Attempts at N4-and O-functionalisation of 91 82

2.2.4 Ketalisation of pentacyclic lactone 85 86

2.2.5 Reduction of pentacyclic lactone 85 89

2.2.6 Alternative routes to the alstonerine E-ring 92

2.2.7 Total synthesis of type A macroline-related alkaloid alstonerinal 138 95

2.2.8 Synthesis of N4-tosyl-macroline 152 99

2.2.9 Towards the synthesis of (±)-alstolactone 101

2.2.10 Synthesis of N4-tosyl-(±)-anhydromacrosalhine-methine 7 103

2.2.11 Total synthesis of (±)-alstonerine 106

2.2.12 Improved route to N4-tosylanhydromacrosalhine-methine 157 113

2.2.13 Extension of methodology 114

2.2.14 Conclusion 118

2.2.15 Future Work 120

Chapter 3. Experimental 123

3.1. General experimental procedures 124

3.1.1 Procedures from the synthesis of hydroxymethyl-substituted aziridine 82 125

3.1.2 Procedures from the synthesis of sulfone 88 131

3.1.3 Procedures from sulfone stability and aziridine reactivity (Sections 2.1.7-2.1.9) 135

3.1.4 Procedures from initial work towards the synthesis of key intermediate 138

lactam–alcohol 90 (Sections 2.1.6-2.1.13)

3.1.5 Procedures from final synthesis of key intermediate lactam–alcohol 90 150

(Sections 2.1.14)

3.1.6 Procedures from synthesis of pentacyclic lactone 85 (Sections 2.2.1 and 2.2.2) 156

3.1.7 Procedures from attempted synthesis of functionalised pentacyclic lactone 165

(Sections 2.2.3-2.2.6)

3.1.8 Procedures from total synthesis of type A macroline-related alklaloid 175

alstonerinal 138 (Section 2.2.8)

3.1.9 Procedures from synthesis of N4-tosyl macroline 152 (Section 2.2.8) 180

3.1.10 Procedures from progress towards total synthesis of alstolactone 184

(Section 2.2.9)

3.1.11 Procedures from synthesis of N4-tosyl anhydromacrosalhine-methine 157 188

(Section 2.2.10)

3.1.12 Procedures from total synthesis of alstonerine 4 (Section 2.2.11) 189

3.1.13 Procedures from extension of methodology (Section 2.2.13) 195

Chapter 4. Appendix 205

4.1 X-ray crystallography data 206

4.1.1 108a 206

4.1.2 108b 212

4.1.3 118 218

4.1.4 133 247

4.2 References 253

Copyright Declaration

‘The copyright of this thesis rests with the author and is made available under a Creative

Commons Attribution Non-Commercial No Derivatives licence. Researchers are free to copy,

distribute or transmit the thesis on the condition that they attribute it, that they do not use it for

commercial purposes and that they do not alter, transform or build upon it. For any reuse or

redistribution, researchers must make clear to others the licence terms of this work’

Originality Declaration

I certify that the work presented in this thesis is solely my own, except where explicitly stated

and appropriately referenced.

Richard Pett

Acknowledgments

I would firstly like to thank Professor Donald Craig for giving me the opportunity to undertake

my postgraduate research under his guidance. It has been a genuine pleasure to work for such an

enthusiastic and knowledgeable supervisor, whose door was always open, and whose company

was always fantastic when enjoying an occaisonal beer with us! I should also use this

opportunity to thank Doctor Chris Braddock, who was an exceptional second mentor and

provided useful feedback throughout my Ph.D. Thanks too, to Doctor Fred Goldberg, especially

for his efforts in organising my CASE placement and providing guidance whilst at AZ, but also

for taking Don and myself out for the occasional lunch!

I would like to thank my family for their continued love and support. I hope that they are aware

that I would have been completely lost without the three of them over the duration of my studies,

especially whilst in transit and when needing to release a little bit of chemistry-related anger over

the phone! I consider myself very lucky to have such an amazing Mum, Dad and Dog (Bruno), I

love you all very much. I suppose at this point I should mention my wonderful sister too, she has

always been there for me and is also a really great friend.

Moving on to the DC group, I should say that I have enjoyed the company of every DC group

member that I have ever met. Those that I have had the pleasure of sharing the Thorpe lab with

will always be fondly remembered, particularly for their appalling tastes in music, excellent

ability to orgainse fun and, in one instance, for a love of a particular glass instrument that came

to a horrible death whilst in my care. It was a pleasure introducing you to the music that ‘the

kids’ are listening to these days, and I will miss listening to Westlife: The Greatest Hits whilst

working late! This CD has now been passed down to Honey Boo Boo Tobes, to whom I hope it

will bring hope in moments of despair as it has done for me. From the moment I arrived in the

DC group, Niels, Simon and the three-headed monster were brilliant company, I believe that I

had visited the Holland Club with Niels and met Coco long before I had seen the NMR

machines. Simon was deliciously inappropriate from day one, and continues to produce moments

of filthy genius to this day. Jenny Lachs is certainly a lucky lady! Having already mentioned the

three heads collectively, I feel that I should thank each one of them individually for being such

great companions throughout our days in the DC group. In no particular order, here goes: I

quickly learnt that apart from at concerts and, on rare occasions, Champions League matches,

that Claire is actually is great fun!! Although not my favourite Doyle, I was always glad to see

her when forced into taking tea breaks. Moving on to Shu, as I am currently making a wage from

being her whipping boy I will keep it positive. I feel that Shu has shown all of the attributes that

a chemist should possess, the ability to consume large quanitites of meat, coffee-proof footwear,

a taste for bitter lemon, a brown pooh-car that is usually in desperate need of a wash and

possession of an incredible JoJo ‘Hiiiyaaaa’ impersonation. I sincerely thank you for being a

great friend throughout our days in the Thorpe lab. This brings us on to the final head. I would

like to thank her for adopting the ‘suns out buns out’ policy whenever possible; many a DC

group sailor was lost at sea to that blue top! She was also responsible for such things as the DC

group bondage calendar, the muurrdumps wiigstouunn, cheeseman and introducing me to drum

n’ bass Friday! As with the other two, I am genuinely grateful to you for looking after me during

my Ph.D, it would not have been the same without you!

Now to the young’uns, namely Madamme JoJo, HBBT, Lee ‘Sm***y D**K Walsh, Alex and

Lewis. Joe, as well as being a fashion and chemistry icon to so many, you also managed to find

time to introduce me to pie balms and other sayings/traditions that the southern softies within the

group could not handle! My thanks to you for being a fabulous laugh, chemist and friend, ever

since I informed you about how great the lab was innit during your open day. I am glad that I

leave you in the company of the talented HBBT. Any man that is willing to rip a good pair of

Chino’s to squat a colleague is a winner in my book, even if that success eluded you on the flash

tennis court!! Lee should be congratulated on his efforts in this field, although he always better at

flash pennas than tennis. I will always remember his boring stories, lad nights out, odours

appendage. Thank you to the remaing PP group members for adding to the fond memories of the

lab for me, including Professor Phil Parsons, who was especially good fun after a viva lunch.

Finally I would like to thank those that have been unfortunate enough to cohabit with me during

the past few years. Thank you to Jack and James for being great housemates and teaching me

about purchase and how not to deal with pigeons! Thanks to Sheena and Dave for offering me

shelter for the jip storms, and finally to Becca, my rock, my world….. Ha! In all seriousness I

would probably still love you even if you stopped bringing home the bacon and putting a roof

over my head, although I wouldn’t risk it.

List of abbreviations

Ac acetyl

app. apparent

Ar aryl

aq. aqueous

BBN 9-borabicyclo[3.3.1]nonane

br. broad

bp boiling point

Bn benzyl

Boc tert-butyloxycarbonyl

Bu butyl

Bz benzyl

Cbz benzyloxycarbonyl

cat. catalytic

CI chemical ionisation

CSA camphorsulfonic acid

d doublet

DBU 1,8-diazobicyclo[5.4.0]undec-7-ene

DCC N,N’-dicyclohexylcarbodiimide

dd doublet of doublets

ddd doublet of doublet of doublets

DIBAL diisobutylaluminium hydride

DMAP 4-dimethylaminopyridine

DME dimethoxyethane

DMF N,N-dimethylformamide

DMS dimethylsulfide

DMSO dimethylsulfoxide

dr diastereomeric ratio

dt doublet of triplets

EDG electron donating group

ee enantiomeric excess

EI electrical ionisation

equiv. equivalents

ESI electrospray ionisation

Et ethyl

EtOAc ethyl acetate

EtOH ethanol

EWG electron withdrawing group

h hour(s)

hex hexyl

HMBC heteronuclear multiple bond correlation

HMDS hexamethyl disilazide

HOMO highest occupied molecular orbital

i iso-

IR infra-red

LDA lithium diisopropylamide

LUMO lowest occupied molecular orbital

m multiplet

m-CPBA meta-chloroperbenzoic acid

Me methyl

MeOH methanol

min minute(s)

m.p. melting point

Ms methanesulfonyl

n neo-

Np naphthalene

NCS N-chlorosuccinimide

NMR nuclear magnetic resonance

Ns 2- or 4-nitrobenzenesulfonyl

o- ortho-

p- para-

Ph phenyl

PTAB phenyltrimethylammonium tribromide

Pr propyl

PrOH propanol

q quartet

Rf retention factor

rt room temperature

s singlet

s sec-

t triplet

tt triplet of triplets

t tert-

TBAF tetrabutylammonium fluoride

TBS tert-butyldimethylsilyl

td triplet of doublets

Tf trifluoromethanesulfonate (triflate)

TFA trifluoroacetic acid

THF tetrahydrofuran

TLC thin layer chromatography

TMA trimethylaluminium

Tol tolyl

Ts para-toluenesulfonyl

tt triplet of triplets

υmax infrared absorption maximum

wt weight

Stereochemical notation

Throughout this report, the Maehr convention of indicating relative and absolute stereochemistry

has been adopted.1 Hence, solid and broken lines are used to denote racemates, whilst solid and

broken wedges are used to denote absolute configuration. Furthermore, the narrowing of both

solid and broken wedges implies increasing distance from the viewer.

Illustration of the Maehr convention

Introduction

11

Chapter 1

Introduction

Introduction

12

1.1 Introduction to macroline, sarpagine and ajmaline-related indole alkaloids

A huge variety of indole alkaloids are known,2 and to date there is still a great deal of interest in

their synthesis.3 Although synthetic approaches towards alstonerine are the main focus of this

report, frequent reference will be made to the synthesis and structures of other members of this

class of alkaloid, which can be categorised into three families, those related to macroline 1,

sarpagine 2 or ajmaline 3 (Figure 1).

Figure 1. Skeletal numbering of parent alkaloids according to LeMen and Taylor.

The biogenetic skeletal numbering proposed by LeMen and Taylor4 is used throughout this

report (Figure 1). The most significant structural similarity shared by all three families in this

class of alkaloids is the indole-annulated azabicyclo[3.3.1]nonane structure.

Macroline-related alkaloids are defined as those having the same skeletal connectivity as

macroline 1. They crucially do not possess an N4–C21 linkage.

Sarpagine-related alkaloids are defined as those having the same skeletal connectivity as

sarpagine 2, specifically with an N4–C21 linkage and the C16-(R) configuration shown.

Ajmaline-related alkaloids are defined as those having the same skeletal connectivity as ajmaline

3, also with an N4–C21 linkage and with C16-(S) configuration epimeric to that of sarpagine as

shown.

Alkaloids that contain substituents at the C16 position are known, as are spirocyclic alkaloids

that contain C7–C17 bonds and thus saturated C2–C7 indole bonds. These compounds may

contain both N1- and N4-substitution, and possess indole ring oxygenation to give spirocyclic

oxindole alkaloids, which can be considered an important class of natural products in their own

Introduction

13

right.5,6

Dimeric alkaloids that contain at least one macroline, sarpagine or ajamaline subunit are

commonly referred to as bis(indole) alkaloids.

Whereas ajmaline and sarpagine have both been isolated from Rauvolfia serpentina,7 macroline

itself has never been isolated from natural sources. However it is believed that macroline is a

likely biosynthetic precursor of various macroline- and sarpagine-related alkaloids.

The field of macroline, sarpagine and ajmaline-related alkaloids was reviewed extensively by

Cook in 19948 and 1995

9, by Lounasmaa in 1999

10 and 2001

11, and by Lewis in 2006

12. These

provide synthetic endeavours relevant to the field in addition to an introduction to the species

from which these alkaloids are isolated (mostly Rauvolfia and Alstonia species).

The focus of this report will be the macroline-related indole alkaloid alstonerine 4, whose

previous syntheses are herein discussed.

1.1.1 Alstonerine

Alstonerine 4 is a macroline-related indole alkaloid which has shown cytotoxic activity against

human lung cancer cell lines,13

and can be isolated from numerous species of Malayan Alstonia,

including Alstonia mycrophylla, Alstonia muelleriana and Alstonia angustifolia. It was first

isolated in 1959 from the bark of Alstonia mycrophylla by Elderfield and Gilman.14

The absolute configuration of (–)-alstonerine 4 was confirmed by the biomimetic synthesis of

LeQuesne et al. in 1969.15

Here, a sample of macroline was converted into alstonerine using an

epoxidation, Michael reaction, and dehydration. As these reactions had ample biochemical

precedent, the synthesis was regarded as biomimetic and, since the absolute configuration of

macroline was known (from that of villalstonine), the absolute configuration of alstonerine 4 was

inferred.

http://en.wikipedia.org/wiki/Rauwolfia_serpentina

Introduction

14

Scheme 1. Biomimetic synthesis of alstonerine 4 from macroline 5.

a) tBuOOH (excess) in MeOH, benzene, then Triton B; b) Freshly prepared P2O5, 24 h.

Alstonerine has since been the subject of significant total synthesis effort, most notably by Cook

and co-workers,3 with significant contributions also from the groups of Martin

3 and others.

3

These synthetic approaches, as well as those previously attempted within the Craig group, are

discussed in this section.

The aim of this introduction is to highlight the methods used previously to construct both the

azabicyclo[3.3.1]nonane core and the adjoining C20 acylated glycal E-ring, so that comparisons

can be drawn to our synthesis, whose details are reported in chapter 2.

Introduction

15

1.2 Cook’s approach to (–)-alstonerine and related compounds

Central to Cook’s work in this area of alkaloid synthesis was tetracyclic ketone intermediate 6

(Figure 2), which was used to synthesise numerous macroline/sarpagine/ajmaline-related

alkaloids, including (–)-alstonerine 4,16

(–)-anhydromacrosalhine-methine 7,17

(–)-macrocarpamine 8,18

(–)-ajamaline 3,19,20,21

and alkaloid G 9.21

Although the synthesis of

tetracyclic ketone 6 has been reviewed previously,3,9

we will discuss why its synthesis allowed

Cook to access so many members of this natural product family.

Figure 2. Selection of alkaloids synthesised from Cook’s common intermediate 6.

1.2.1 The tetracyclic ketone intermediate

For the synthesis of tetracyclic ketone 6 from D-tryptophan 10, Cook and co-workers used

sequential Pictet–Spengler22

and Dieckmann cyclisations to build the C- and D-rings in the 4th

and 5th

steps respectively.16

As the first three reactions of the synthesis were protection steps, the

azabicyclo[3.3.1]nonane motif was established at the very beginning of the synthesis. The

Introduction

16

synthesis of tetracyclic ketone 6a is outlined below (Scheme 2, below). It is worth noting that

intermediate 6 includes the same (S)-configuration at the C5 position that is found in natural

L-tryptophan. However it was synthesised using the unnatural amino acid D-tryptophan, which

contains the (R)-configuration at this position. D-Tryptophan was used as a variety of bulky

aldehydes had previously entered into stereoselective Pictet–Spengler cyclisations with N4-

benzyltryptophan methyl esters, to give only the corresponding trans-1,3-disubstituted-1,2,3,4-β-

carbolines.23

Having noted this preference, Cook purposely used the (R)-configured Pictet–

Spengler substrate 11 to install the correct C3 stereochemistry in tetrahydro-β-carboline methyl

esters 12.

Scheme 2. Key intermediate in Cook’s approaches to macroline-related indole alkaloids.

a) Na/NH3(l), MeI; b) HCl, MeOH, 80% over two steps; c) PhCHO, MeOH, then NaBH4, –5°C, 88%; d) 14,

benzene/dioxane, Δ, then HCl, MeOH reflux, 80%; e) NaH, MeOH, toluene, reflux, 92%; f) aqueous HCl, AcOH,

reflux, 91%.

The first stage of Cook’s synthesis of the tetracyclic ketone intermediate was to form the C-ring

and install the correct C3 stereochemistry. D-Tryptophan derivative 11 was heated with

2-ketoglutaric acid 14, which gave a disappointing diastereomeric ratio of cis- and

trans-tetrahydro-β-carboline monoacids (42:58 12a:12b, R = H, Scheme 3, below).24,25

An

enhanced diastereomeric ratio in favour of trans-tetrahydro-β-carboline methyl esters 12

(28:72 12a:12b, R = Me, Scheme 3) was achieved using methyl 3-formylpropionate 15.26

This

Introduction

17

also removed a trivial esterification step from the synthesis; however the trans-selectivity

remained insufficient for large scale synthesis.

Scheme 3. Cook’s strategy level C-ring forming Pictet–Spengler.

a) As before, 2-ketoglutaric acid 14, benzene, 80%; b) methyl-3-formylpropionate 15, benzene.

A large-scale enantiospecific route to the desired trans-diastereomer 12b was eventually

achieved using a post-Pictet–Spengler acid-mediated C3 isomerisation.3 This allowed the

cis-diastereomer of either monoacid 12a (R = H, Scheme 3), or diester (R = Me, Scheme 3) to

be epimerised into the more stable trans-isomer 12b. This was achieved by heating 12a in

methanolic HCl, which caused fragmentation of the N4–C3 bond and gave stabilised ‘allylic’ C3

carbocation 16 that could undergo rotation and recyclisation. This allowed unfavourable

(1,3)-diaxial interactions to be minimised, as shown below (Figure 3).

Figure 3. Acid-mediated epimerisation of C3,C5-cis-tetrahydro-β-carboline 12a.

Having devised an efficient route to intermediate 12b from D-tryptophan, it remained to invert

the C5 stereochemistry in order to attain the cis-1,3-disubstituted carboline methyl ester 17

(Scheme 4, below), that was required for the Dieckmann cyclisation to complete the

azabicyclo[3.3.1]nonane motif. The C5 epimerisation and Dieckmann cyclisation steps were

achieved in a one-pot process by treating trans-12b with sodium methoxide.16

This effected

reversible formation of the less favourable cis-diastereomer 17, whose cis-configuration allowed

an irreversible Dieckmann cyclisation to occur. This forced the equilibrium to the right and

Introduction

18

favoured formation of the desired tetracyclic β-keto esters 13. The synthesis was completed by

acid-mediated decarboxylation, which yielded Cook’s ubiquitous intermediate, tetracyclic ketone

6a in 47% over seven steps.

Scheme 4. C5 epimerisation and Dieckmann cyclisation of 12b.

a) NaOMe, toluene, reflux, 92%; b) aqueous HCl, AcOH, reflux, 91%; c) MeOTf, then H2/Pd/C, 80% over two

steps.

Introduction

19

1.2.2 Cook’s first approach to (–)-alstonerine

In Cook’s first approach, (–)-alstonerine was synthesised from tetracyclic ketone 6 using a

10-step sequence that utilised the C16 ketone functionality in 6 as a reactive handle to access the

E-ring.16

Excluding the required functional group interconversion (N4-deprotection and

methylation), the azabicyclic core motif remained untouched from its synthesis in steps 4 and 5.

The preinstalled azabicyclo[3.3.1]nonane structure of the tetracyclic ketone intermediate 6 was

used to direct a stereospecific Claisen rearrangement and hydroboration, which generated the

required C15 and C16 stereochemistry respectively.

Figure 4. Key intermediates in Cook’s first synthesis of the alstonerine E-ring.

The synthesis of the Claisen rearrangement substrate is outlined below (Scheme 5, Page 20).

N4-Benzyl protected tetracyclic ketone 6a was first converted into the N4-methyl derivative 6

using methyl triflate and palladium-catalysed debenzylation conditions.28

At this stage, the C16

ketone functional group was homologated to α,β-unsaturated aldehyde 20 and reduced to the

corresponding allylic alcohol using LiAlH.

The homologation was achieved by reacting 6 with the anion of α-chloromethyl phenyl

sulfoxide, generating a chlorohydrin intermediate that gave spirooxirane phenyl sulfoxide 19

upon base-induced cyclisation. It was the spiroepoxide 19 that was homologated using lithium

perchlorate and tri-n-butylphosphine oxide. The synthesis of the Claisen substrate was completed

by alkylation with butyn-3-one 21, which gave enone 18 in 60% yield over four steps from

tetracyclic ketone.

For the Claisen rearrangement, enone 18 was converted into the desired β-keto aldehyde 22 with

the natural C15 stereochemistry, by heating 18 in benzene in a sealed tube at 145°C.27

The

stereoselectivity of the rearrangement was rationalised by presuming a chair-like transition state

Introduction

20

18a, with attack occurring from the α-face of the azabicyclo[3.3.l]nonane system

(Scheme 5, below).

Scheme 5. Elaboration of tetracyclic ketone by Claisen rearrangement

a) PhS(O)CH2Cl, LDA, THF then KOH, 86%; b) LiClO4, Bu3P(O), toluene, reflux, 84%; c) LiAlH, Et2O, −20C,

90%; d) Et3N, 21, dioxane, dark, 90%; e) benzene, 145C, sealed tube, 65%.

Following the success of the Claisen rearrangement, a variety of approaches at completing the

E-ring synthesis by chemoselective reduction proved difficult.28

Numerous attempts at protecting

the two carbonyl groups as acetal derivatives failed, as did attempted chemoselective reductions

of the β-keto aldehyde to the corresponding β-hydroxy ketone using various borane reagents.

Oxidation of the aldehyde functionality to the carboxyl equivalent also proved futile. Following

numerous failed attempts at protecting or chemoselectively oxidising or reducing the

β-dicarbonyl functionality, it was decided instead to attempt a hydroboration–oxidation of the

exomethylene group to yield a triol intermediate (Scheme 6, below).

Eventually, β-dicarbonyl 22 was reduced to triol 23 in two steps, by firstly reducing the

β-dicarbonyl using sodium borohydride, followed by hydroboration–oxidation of the exocyclic

methylene function with 9-BBN, H2O2/NaOH which was presumed to have occurred from the

top face of the alkene.28

Introduction

21

With triol 23 in hand, the E-ring skeleton was achieved by a one-pot tosylation and

base-induced cyclisation process that gave tetrahydropyrans 24. These were converted into an

approximately 1:1 mixture of dihydroalstonerine 25 and alstonerine 4, via a modified Swern

oxidation. The poor selectivity of this reaction could be improved to a certain extent, by reducing

the ketone functionality of dihydroalstonerine 25, and resubmitting the resulting

tetrahydropyrans 24 with the C19 alcohol to the modified Swern reaction. This allowed for an

increase of up to 51% and gave alstonerine in an overall yield of 4.2% over 18 steps from

D-tryptophan. Of these steps, ten had been required to synthesise the E-ring from N4-benzyl

tetracyclic ketone 6a, in 6.2% yield.16

Scheme 6. Conclusion of Cook’s first E-ring synthesis via selective hydroboration and oxidation

level manipulation.

a) NaBH4, EtOH, 80%; b) 9-BBN, THF, rt, 20 h then NaOH, H2O2, 40°C, 2 h, 85%; c) TsCl, pyridine then Et3N, rt,

60%; d) COCl2, DMSO, CH2Cl2, –78°C→–10°C, then Et3N, 51% after recycling SM.

From Cook’s first synthesis, it can be seen that whilst the azabicyclic[3.3.1]nonane core was

readily accessed using successive Pictet–Spengler and Dieckmann cyclisations, the adjoining

C20 acylated glycal E-ring was a challenging motif to synthesise, with multiple oxidation level

adjustments required to complete its synthesis via Cook’s Claisen approach.

Introduction

22

1.2.3 Cook’s second approach

In 2005, Cook published a second approach to alstonerine that again used tetracyclic ketone 6a

as an advanced intermediate.29

However the construction of the E-ring was achieved by a

completely novel approach that also provided a route to macroline, and allowed entry to

sarpagine-related alkaloids.

Azabicyclic tetracyclic ketone 6a was converted into alstonerine via naturally occurring

sarpagine related alkaloid N1-methylvellosimine 26, which was then converted into the

Tsuji–Wacker substrate 27 using a six-step sequence (Scheme 7, below). This approach used a

novel modification of Tsuji–Wacker oxidation conditions to convert the α-substituted

α,β-unsaturated ketone 27 into alstonerine. The overall synthesis again required a total of 18

steps, and provided the natural product in an improved 10% overall yield from D-tryptophan.

Figure 5. Key intermediates in Cook’s second approach.

Cook’s second approach again used a 10-step sequence to convert tetracyclic ketone 6a into the

penultimate intermediate, which in this case was the Tsuji–Wacker substrate 27. Advantageous

to this synthesis was the selectivity of the final oxidation step. Whereas the final step in Cook’s

first approach produced the natural product 4 and related dihydroalstonerine 25 in an

approximately 1:1 ratio, the Tsuji–Wacker reaction gave alstonerine as the only product in 60%

yield.29,30

The first stage of Cook’s second E-ring synthesis was to convert tetracyclic ketone into affinisine

28 via N1-methylvellosimine 26, both of which have the same skeletal connectivity as sarpagine

2, including the N4–C21 linkage and (R)-configuration at the C16 position. This was achieved

using the procedure outlined by Liu in 2002 (Scheme 7, below).31,32

Introduction

23

Tetracyclic ketone 6a was converted into Heck substrate 30 using the previously successful

catalytic hydrogenation debenzylation, followed by treatment with (Z)-1-bromo-2-iodo-2-butene

29. This gave alkylated ketone 30 in 85% yield over two steps.33

30 was converted into

N1-methylvellosimine 26, by palladium-catalysed α-vinylation using modified

Buchwald–Hartwig arylation conditions as reported by Muratake and Natsume.34

This

enolate-driven cyclisation took place stereospecifically and afforded N4–C21 fused 26 in 82%

yield.33

Having established the sarpagine skeleton, N1-methylvellosimine 26 was converted into

affinisine 28 using Wittig conditions followed by borohydride aldehyde reduction (Scheme 7).35

Following O-silyl protection, the ethylidene moiety in affinisine 28 was converted into ketone 31

by hydroboration–oxidation and then Dess–Martin oxidation. 31 was converted into O-silyl

protected macroline by N4-methylation and elimination. This gave the Tsuji–Wacker substrate 27

in an overall yield of 21% from tetracyclic ketone 6a.

Scheme 7. Cook’s second approach to alstonerine.

a) H2/Pd/C, then HCl, EtOH; b) Z-1-bromo-2-iodo-2-butene 29, K2CO3, reflux, 85% over two steps; c) Pd(dba)2

(2 mol%), DPEphos (2.2 equiv.), tBuONa, THF, 70C, 82%; d) MeOCH2Ph3PCl, KO

tBu, benzene, rt, 24 h; e) HCl,

THF, 55°C, 5 h, 65% over two steps; NaBH4, EtOH, 0°C; f) TIPSOTf, 2,6-lutidine, CH2Cl2, 0C; g) BH3/Me2S

(9.0 equiv.), THF, rt, 3 h, then NaOH/H2O2, rt, 2 h; HOAc, THF, reflux; h) Dess–Martin periodinane, CH2Cl2, 0C,

63% over three steps; i) MeI, THF, then tBuOK, EtOH, THF, reflux, 90%.

Introduction

24

The synthesis was completed using a novel modification of the Tsuji–Wacker oxidation to

convert α-substituted α,β-unsaturated ketone 27 into (–)-alstonerine. Importantly, this one-pot

cascade reaction gave alstonerine as the only product, in 60% yield (Scheme 8).

Scheme 8. Oxidation of O-protected macroline to (–)-alstonerine 4.

a) Na2PdCl4, (40 mol%), tBuOOH (1.1 equiv.), HOAc:H2O;

tBuOH (1:3:3), 80°C, 60%.

Cook’s second approach to alstonerine led to an improved overall yield of 10% from

D-tryptophan. Although the E-ring was synthesised in the same number of steps as the first

approach, Cook’s second approach provided access to the sarpagine related alkaloids as well as

using a more versatile late stage intermediate 27, which could be converted into both macroline

and alstonerine. This in turn provided access into the bis(indole) alkaloids, as highlighted by the

improved synthesis of macralstonine 32 (Scheme 9).36

Scheme 9. Synthesis of bis(indole) alkaloid macralstonine 32.

a) Alstophylline 33, 0.2 N HCl.

Introduction

25

1.3 Kuethe’s aza-Diels–Alder approach

In 2002, Kuethe et al. reported an approach to the tetrahydro-β-carboline skeleton of the

ajmaline/sarpagine alkaloids that used as key steps an aza-Diels–Alder and intramolecular Heck

cyclisation to synthesise the D- and C-rings respectively.37

This approach provided relatively

rapid access to the azabicyclo[3.3.1]nonane motif, with tetracyclic intermediate 37 being

synthesised in just 4 steps from 2-(1-methylindol-3-yl)- ethanol 34, in an overall yield of 28%

(Scheme 10).

Scheme 10. Kuethe’s aza-Diels–Alder/Heck based synthesis of the C- and D-rings.

a) n-BuLi, MTBE, reflux, then I2, 0°C; b) Dess–Martin, 47% over two steps; c) 38 (1.3 equiv.), Zn(OTf)2

(1.1 equiv.), BnNH2 (1.1 equiv.), CH2Cl2, rt, 3 h, 70%; d) PdCl2(CH3CN)2 (1.0 equiv.), tBu3P (2.0 equiv.), MeCN,

reflux, 85%.

Having established a short, but moderate-yielding synthesis of 37, an attempt to extend the

methodology by introducing the E-ring was investigated. To this end the C16 hydroxymethyl-

substituent was introduced by an aldol reaction with formaldehyde prior to the Heck cyclisation.

Presumably this was attempted prior to formation of the C-ring, as the analogous reaction of

tetracyclic substrate 40 suffers from a facile retro-aldol, as we have found in the Craig group

(Scheme 21, Page 39). Kuethe was able to introduce the hydroxymethyl substituent in the C16

Introduction

26

position by reacting the lithium enolate of 36 with paraformaldehyde, which gave β-hydroxy

substituted pyridone in 67% yield and mentioned no observation of C2 lithium halogen

exchange. β-Hydroxymethyl substituted pyridone 39 was converted into a ~ 1:1 mixture of

tetracyclic 40 (33%) and exomethylene compound 41 (29%) using Heck conditions.

(Scheme 11)

Scheme 11. Kuethe’s aza-Diels–Alder/Heck based synthesis of the C- and D-rings.

a) LiHMDS, (CH2O)n, –20°C, 67%; b) Pd2(dba)3, tBu3P, DMF, 100°C, 33% + 41 29%.

Using this approach, Kuethe was able to synthesise β-hydroxymethyl substituted pyridone 40

from 2-(1-methylindol-3-yl)-ethanol 34 in 6.8% yield over 5 steps. Thus, this approach offers

rapid access to the azabicyclo[3.3.1]nonane motif. However, previous work within the Craig

group (as discussed later on Page 39) had shown that converting β-hydroxymethyl pyridone 40

into (–)-alstonerine was difficult.

Introduction

27

1.4 Kwon’s phosphine-catalysed [4+2] annulation synthesis

Also published in 2005, Kwon reported a formal synthesis of (±)-alstonerine38

that used a

strategy based upon a series of phosphine-catalysed [4+2] annulation reactions between imines

42a and allenes 43a that had been reported by the group in 2003 (Scheme 12).39

Scheme 12. Kwon’s phosphine-catalysed [4+2] annulation approach to tetrahydropyridines 44a.

a) Bu3P (20 mol%), CH2Cl2, 86–98% depending on R group variant.

This methodology was used to synthesise the intermediate 45 that contained the carbon skeleton

of the azabicyclo[3.3.1]nonane motif (Scheme 13, below).38

Scheme 13. Kwon’s phosphine-catalysed [4+2] annulation approach to tetrahydropyridine 44.

a) Bu3P (30 mol%), CH2Cl2, rt, 73% d.r. 3:1 ; b) HCl, EtOAc, 90%.

Tetracyclic intermediate 45 was converted into Cook’s allylic alcohol intermediate by reducing

the carbonyl moieties and N4-deprotection–methylation. The D-ring was synthesised using the

[4+2] annulation methodology by reacting imine 42 with allene 43. This gave diastereomeric

esters 44 with correct C3 stereochemistry in good yield. The azabridged C-ring was formed via

acid-catalysed intramolecular Friedel–Crafts acylation, which gave tetracyclic 45 in excellent

yield.

Having established the azabicyclic core motif, tetrahydropyridine 45 was converted into Cook’s

intermediate 47 in a yield of 66% over 5 steps. (Scheme 14, below) The N4-nosyl

Introduction

28

deprotection–methylation sequence was completed using Fukuymama denosylation conditions40

followed by Eschweiler–Clarke methylation.41

The chemoselective reductive deoxygenation of

the C6 ketone group was eventually achieved using zinc-modified cyanoborohydride conditions.

This gave a N4–cyanoborane complex that was converted into the tertiary amine by refluxing in

ethanol. The sequence was completed by reducing the α,β-unsaturated ester to allylic alcohol 47,

which had been converted (Cook’s first approach) into a mixture of dihydroalstonerine and

alstonerine in 6 steps. (Scheme 5, Page 20) This equated to a 9-step synthesis of the alstonerine

E-ring from Kwon’s N4-methylated tetracyclic intermediate 46 (Scheme 14).

Scheme 14. Completion of Kwon’s formal synthesis.

a) PhSH, K2CO3, DMF, 99%; b) 35% aqueous HCHO and 88% aqueous HCO2H, reflux, 99%; c) NaBH3CN/ZnI2,

CH2Cl2, reflux, 74%; d) EtOH, reflux, 98%; e) DIBAL, toluene, –73°C, 92%.

Introduction

29

1.5 Martin’s Pauson–Khand Synthesis

In 2007 the group of Prof. Martin at the University of Texas published a synthesis of

alstonerine42

that stemmed from their interest in alkaloid synthesis via transition metal-catalysed

cascade reactions.43

Whilst working on an enyne metathesis approach to a range of alkaloids

containing azabicyclic core motifs, they became interested in the Pauson–Khand reactivity of

their enyne metathesis substrates. The feasibility of such an approach was quickly proven using

enyne 48a, which gave the azabicyclo[3.3.1]nonane system 49a as a single diastereomer.

(Scheme 15)

Scheme 15. Pauson–Khand azabicyclo[3.3.1]nonane synthesis 49a.

a) Co2(CO)8, DMSO, THF, 65°C, 89%.

Having established the viability of his Pauson–Khand approach, Martin built his total synthesis

of alstonerine around the construction of the indole annelated azabicyclo[3.3.1]nonane core

motif from enyne 48 (Scheme 16, below). Whereas Cook’s approaches had required additional

epimerisation reactions to synthesise the azabicyclo motif as a single enantiomer, Martin was

able to achieve this in a single high yielding step as a single enantiomer via his strategy level

Pauson–Khand reaction (Scheme 16).

Scheme 16. Martins key step. The Pauson–Khand reaction of enyne 48.

a) Co2(CO)8, DMSO, THF, 65°C, 94%.

Introduction

30

This powerful reaction allowed Martin to synthesise alstonerine in just fifteen steps from

L-tryptophan. This was a shorter route than either of those reported by Cook, but the overall yield

of his synthesis was diminished by the disappointing yields of the two sequences adjoining the

high yielding and selective Pauson–Khand step.

The first problem that Martin faced was the synthesis of the Pauson–Khand substrate, enyne 48

(Scheme 17, below). This was synthesised from natural L-tryptophan using a four-step sequence,

in which the C-ring was synthesised in the very first step of his total synthesis. Martin used a

Bischler–Napieralski-like reaction, whereby L-tryptophan was first acylated with acetic

anhydride and then heated with excess formic acid and concentrated HCl, to give carboline 50 in

63% (crude yield) as a single enantiomer. With the C-ring established, diastereomeric aminals 51

were produced in one pot by treating 50 with benzylchloroformate and methanol in the presence

of triethylamine. BF3-mediated allylation gave a 5.5:1 mixture in favour of cis-carboline 52. At

this stage, a novel one-pot partial DIBAL reduction/Ohira–Bestmann reaction was used covert

methyl ester 52 into enyne 48. This provided the Pauson–Khand substrate in 18% yield from

L-tryptophan.

Scheme 17. Synthesis of Pauson–Khand substrate enyne 48.

a) Ac2O, HCO2H, rt, then conc. HCl, 55C, 63%; b) Cbz-Cl, Et3N, CH2Cl2, −20C, then MeOH, Et3N, rt, 76%;

c) allyl-TMS, BF3·OEt3, CH2Cl2, 0C, 72%; d) DIBAL, toluene, −78C, then MeOH, NaOMe and O–B reagent,

−78C→rt, 55%.

Introduction

31

Having established a short synthetic sequence to pentacyclic enone 49, and with the correct

azabicyclo[3.3.1]nonane motif in place, it remained to synthesise the fifth and final E-ring.

However this again proved difficult, and presented Martin with his second obstacle in the total

synthesis. When numerous attempts at the ring expansion and oxidation of the cyclopentenone

49 by Baeyer–Villiger conditions failed, an alternative oxidative cleavage route was envisaged.

If we again focus on the construction of the E-ring, as illustrated below (Scheme 18), significant

manipulation was required to elaborate the cyclopentenone moiety in 49 to the C20 acylated

glycal structure 56 that was required for the natural product. Following

N1-protection, the enone moiety was converted into silyl enol ether 53 by a stereoselective

hydrosilylation using a platinum divinyltetramethyl disiloxane complex 57 (Karstedt’s catalyst)

and five equivalents of bulky triisopropylsilane. Interestingly, less bulky silanes led to the

formation of significant amounts of the parent cyclopentenone. The required oxidative cleavage

of 53 had failed under ozonolysis conditions and instead silyl enol ether 53 was converted into

δ-lactone 54 using Johnson–Lemieux conditions, followed by borohydride reduction of the

intermediate aldehyde–ester and acid-induced lactonisation. The oxidation, reduction and

lactonisation steps were carried out sequentially without purifying intermediates, giving rise to a

moderate 55% yield. δ-Lactone 54 was first reduced using DIBAL to give an intermediate lactol,

which gave dihydropyran 55 following O-mesylation and elimination. The final stage required

for the E-ring synthesis was the C20 acylation. As Friedel–Craft type conditions led to

competing indole acylation products, N1- and N4-protected dihydropyran 55 was converted into

N1- and N4-protected alstonerine 56 using trichloroacetyl chloride followed by reduction of the

trichloroacetyl moiety of the intermediate.

The synthesis was completed by carbamate deprotection using iodotrimethylsilane and a

sequential N4- and N1-methylation. Thus, the total synthesis was completed in 15 steps from

L-tryptophan in an overall yield of 4.4%. (Scheme 18, below)

Introduction

32

Scheme 18. Martin’s oxidative cleavage approach to the alstonerine E-ring.

a) Boc2O, DMAP, MeCN, 99%; b) 57, iPrSiH, toluene, 80C, 93%; c) OsO4 (10 mol%), NaIO4, acetone:H2O (3:1);

d) NaBH4, MeOH, then TsOH·H2O, CH2Cl2, 55% over two steps; e) DIBAL, toluene, –78C; f) MsCl, Et3N,

CH2Cl2, 61% over two steps; g) ClCOCCl3, pyridine, 65C; h) Zn, AcOH, 75% over two steps; i) TMSI, MeCN,

78%; j) MeI, THF, then NaH, MeI, 72%.

This synthesis represented the first use of the Pauson–Khand reaction to synthesise the

azabicyclic motif of (–)-alstonerine. This step arguably provided a more selective route to the

azabicyclo[3.3.1]nonane core than those previously reported by Cook, which required

epimerisations to allow for the enantioselective synthesis of this motif. This approach, although

shorter than those previously reported by Cook et al., had a significantly lower overall yield, due

largely to the difficulty in synthesising the required enyne Pauson–Khand substrate 48, and the

number of steps required to convert the cyclopentenone into the alstonerine E-ring.

Introduction

33

1.6 The Craig group’s previous approaches to alstonerine

1.6.1 Background

The aziridine motif is highly valuable in the synthesis of nitrogen containing natural products.44

Structurally analogous to epoxides and readily synthesised as single enantiomers,44

they have

found widespread use in asymmetric synthesis due to their ability to undergo both regio- and

stereoselective nucleophilic ring-opening reactions.45

Early work within the Craig group focused

on using aziridines derived from α-amino acids in the assembly of pyrrolidines46

and

piperidines.47

The antifungal agent (+)-preussin 58,48

(+)-monomorine 59 (a trail pheromone of

the widespread pharoah’s worker ant49

Monomorium pharaonis) and cytotoxic marine alkaloid50

lepadiformine 60, are among those natural products synthesised within the Craig group using

aziridine chemistry.46,51,52

Figure 6. Synthesis of nitrogen containing natural products within the Craig group.

During these early synthetic endeavours, aziridine-derived heterocycles, in particular the

1,4-bis(tolylsulfonyl)tetrahydropyridines 61a synthesised from α-amino acids (Figure 7, below),

were found to be useful substrates for an extensive range of synthetic transformations. Their

utility is enhanced by the simple nature of their preparation via aziridine ring-opening reactions

between arylsulfonyl-substituted acetals 62 and α-amino acid-derived N-tosylaziridines 63a,

followed by cyclocondensation (Figure 7).

Figure 7. Synthesis of 1,4-bis(tolylsulfonyl)tetrahydropyridines 61a.

Introduction

34

Tetrahydopyridines 61a have been applied in highly stereoselective, SN1 and SN1’

reactions,53,47(a)

acid-catalysed reduction,47(c)

homo- and hetero-Diels–Alder reactions,54

syn-dihydroxylation47(c)

and intramolecular cyclisation processes,55,47(b),68

and as such, their

usefulness as building blocks in organic synthesis has been proven, as outlined below (Figure 8).

Figure 8. Synthetic applications of 1,4-bis(tolylsulfonyl)tetrahydropyridines 61a.

Having shown tetrahydropyridines 61a to be useful in piperidine synthesis, the Craig group

became interested in the synthesis of the piperidine containing alkaloid natural products,

particularly benzylisoquinoline alkaloid morphine 64, and the macroline-related alkaloids

alstonerine 4 and suaveoline 65 (Figure 9, below).

Introduction

35

Figure 9. Possible applications of tetrahydropyridine chemistry in alkaloid synthesis.

In particular, it was envisaged that the L-tryptophan derived bis(tolylsulfonyl)tetrahydropyridine

61 could be used as an advanced intermediate in the total synthesis of macroline-related

alkaloids, alstonerine 4 and suaveoline 65 (Figure 10, below). For progress on the synthesis of

suaveoline 65, see the theses of Lewis56

and Tholen.57

Figure 10. Original strategy for bis(tolylsulfonyl)tetrahydropyridine 61 as intermediate in

(–)-alstonerine 4 synthesis.

The following discussion describes previous synthesis approaches towards alstonerine as

investigated in the Craig group.

Introduction

36

1.6.2 The Craig group’s first approach to (–)-alstonerine

The approach to alstonerine anticipated that the azabicyclo[3.3.1]nonane containing tetracyclic

ketone intermediate 67 would be synthesised via an acid-catalysed Pictet–Spengler cyclisation of

the L-tryptophan-derived 1,4-bis(tolylsulfonyl)tetrahydropyridine 61. The E-ring would be

installed by a regio- and stereospecific aldol, β-ketoesterification and Knoevenagel reaction of

69. Oxidation level adjustment and FGI would furnish (–)-alstonerine 4.

Figure 11. Retrosynthetic analysis (–)-alstonerine 4.

Introduction

37

Forward Synthesis

In the first attempted total synthesis of (–)-alstonerine 4, Ioannidis58

successfully synthesised

tetracyclic intermediate 66, (Scheme 19, below) without the need to isolate

bis(tolylsulfonyl)tetrahydropyridine 61. This was achieved via a modification of the previously

discussed tetrahydropyridine chemistry, whereby the tetrahydropyridine formation and Pictet–

Spengler cyclisation steps (b and c, Scheme 19) were combined into a tandem process (d,

Scheme 19). Ring-opened intermediate 70 was obtained in >80% yield, by treating

L-tryptophan-derived aziridine 63b with the lithiated carbanion of sulfonyl acetal 62 (Scheme

19).

Various conditions were investigated for the tandem tetrahydropyridine–Pictet–Spengler

cyclisation, starting with those previously reported for the Pictet–Spengler cyclisation of

tetrahydropyridine 6158

(c, Scheme 19). However, TMSI,59

catalytic sulfuric acid47

and TFA

gave only low yields of the desired tetracyclic intermediate 66. Extensive N1TBS deprotection

was also observed under these conditions. The desired tetracycle 66 was eventually made in

good yield, by treating 70 with stoichiometric (±)-CSA in CH2C12 or pTSA in acetone.58

Scheme 19. Tandem tetrahydropyridine formation and Pictet–Spengler cyclisation of 70.

a) 62+ n-BuLi (1.1 equiv.), THF–TMEDA, 0°C→rt, 1 h, >80%; b) (±)-CSA (1.0 equiv.), CH2C12, rt, 1 h, >85% or

para-TsOH (1.0 equiv.), acetone, rt, 30 min, >85%.

Introduction

38

Having successfully optimised the tandem tetrahydropyridine–Pictet–Spengler cyclisation that

installed the C- and D-rings of the azabicyclic core in a single step, and allowed rapid access to

tetracyclic intermediate 66 from L-tryptophan, the final phase of the synthesis required

installation of a C15 ketone moiety in place of the epimeric sulfone group to allow introduction

of the E-ring. Numerous oxidative desulfonylation conditions were investigated.58

The use of

bis(trimethylsilyl)peroxide60

and chlorodimethoxyborane58

both failed. The possibility of Lewis

acid-mediated thionium ion formation followed by hydrolysis was also explored. The α-sulfonyl

anion derived from 66 was quenched with both PhSSPh or PhSSO2Ph (sources of PhS+),

however no dithioketal intermediate 71 was observed. Dithioketal 71 was eventually synthesised

by installing the dithioketal functionality prior to the tandem tetrahydropyridine–Pictet–Spengler

cyclisation.

Ring opened intermediate 70 was converted into dithioketal 72 in only 40% yield, by treating 70

with n-BuLi and PhSSO2Ph. At this stage, dithioketal 72 was converted into the desired

tetracyclic ketone 67 by tandem tetrahydropyridine–Pictet–Spengler cyclisation and aluminium-

mediated diphenylthioketal formation, followed by treatment of 71 with mercury(II)chloride in

the presence of proton scavenger CaCO3.58

Scheme 20. Failed oxidative desulfonylation of tetracyclic intermediate 66.

a) n-BuLi (2.2 equiv.), PhSSO2Ph (1.5 equiv.), THF–TMEDA, 0°C, 40%; b) (±)-CSA (1.0 equiv.), CH2C12, rt, 1 h,

80%; c) Me2AlSPh (3.0 equiv.), CH2C12, rt, 4 h, 55%; d) HgCl2 (2.2 equiv.), CaCO3 (2.2 equiv.), acetone–H2O,

reflux, 12 h, 93%.

Introduction

39

With conditions for the challenging oxidative desulfonylation established, attention turned to

installing the alstonerine E-ring. Unfortunately, the aldol reaction of tetracyclic ketone 67 with

formaldehyde (retrosynthesis, Page 36) was plagued by a facile retro-aldol reaction that was

ultimately responsible for the failure of this approach (Scheme 21, below). Starting material

recovery was always observed under standard aldol conditions. The facile nature of the retro-

aldol was due to the axial orientation of the C16 hydroxymethyl-substituent in 68, which allowed

πC=O→σ*C-C donation and made tetracyclic ketone 67 energetically favourable.

Hydroxymethylation could be achieved using milder conditions outlined by Yamamoto et al.61

whereby TMSOTf and Et3N were used to form the TMS enol ether of 67, which reacted with

methylaluminium bis(2,6-diphenylphenoxide)-formaldehyde complex to give β-hydroxymethyl-

ketone 68 in moderate yield. β-Ketoesterification of 68 using diketene and dioxinone failed,

instead returning tetracyclic ketone 67 via the facile retro-aldol previously highlighted.58

At this

stage, due to the difficulty of the aldol and β-ketoesterification steps required, this approach

towards the E-ring synthesis was abandoned.

Scheme 21. Unavoidable facile retro-aldol of 68.

a) Et3N (4.0 equiv.), TMSOTf (2.0 equiv.), CH2Cl2, 0°C, 15 min, then MAPH-formaldehyde (1.5 equiv.),

–78°C, 2 h, 54%.

Introduction

40

1.6.3 Hetero-Diels–Alder approach

In the original approach, the required azabicyclo[3.3.1]nonane core had very successfully been

installed via a tandem tetrahydropyridine–Pictet–Spengler cyclisation. The limitations of this

approach had all arisen whilst attempting to synthesise the E-ring, namely the oxidative

desulfonylation of 66, subsequent aldol of tetracyclic ketone 67 and β-ketoesterification

reactions, thus an alternative strategy was envisaged that retained the previous synthesis of the

azabicyclic core via tandem tetrahydropyridine–Pictet–Spengler cyclisation, but included a

revised hetero-Diels–Alder approach to the E-ring (Figure 12, below).

Figure 12. Possible synthesis of the E-ring via hetero-Diels–Alder.

For this approach to be successful the Diels–Alder reaction of 73 with formaldehyde would have

to occur from the bottom face of the diene; this would install the correct C16 stereochemistry and

provide pentacyclic substrate 74 from which to complete the synthesis.

The retrosynthesis established for the synthesis of the Diels–Alder diene substrate 73 is shown

below (Figure 13). The azabicyclic core of diene 73 would be synthesised as previously from

di-aldehyde 77 via the acid-catalysed tandem tetrahydropyridine–Pictet–Spengler cyclisation that

had been employed in the previous approach. The tandem cyclisation would be followed by

base-mediated sulfone elimination and protection to give diene 73. The synthesis of intermediate

di-aldehyde 77 would require an alternative nucleophile for the aziridine ring-opening reaction.

Work by Ioannidis58

during the original approach found that sulfonyl nucleophiles were effective

partners for aziridine 63b, and as such cyclopentenyl sulfone 80 was chosen. The double bond in

80 would be used to introduce the di-aldehyde functionality when required.

Introduction

41

Figure 13. Retrosynthetic analysis (–)-alstonerine 4.

Introduction

42

Forward Synthesis

Both Rahn62

and Ioannidis58

showed that intermediate 75 could be obtained via nucleophilic

ring-opening of L-tryptophan-derived aziridine 63b by the sulfonyl anion derived from

bis(phenylsulfonyl)cyclopentene 80. Treatment of bis(phenylsulfonyl)cyclopentene 80 with

freshly prepared lithium naphthalenide solution, followed by addition of aziridine 63b gave

intermediate 75 in 55–64% yield. Dihydroxylation of the cyclopentene containing ring-opening

product 75 using KMnO4 gave the corresponding diol in 61% yield (Scheme 22). Oxidative

cleavage of the resulting 1,2-diol and the acid-mediated tetrahydropyridine–Pictet–Spengler

cyclisation under anhydrous conditions gave the azabicyclo[3.3.1]nonane containing tetracyclic

aldehydes 78 in 94% yield over two steps (Scheme 22).

Scheme 22. Synthesis of tetracyclic aldehyde 78.

a) Li·Np (4.0 equiv.), THF, –20°C, 1,1-bis-(phenylsulfonyl)cyclopent-3-ene 80 (1.2 equiv.), THF, –78°C, then

aziridine 63b (1.0 equiv.), DMPU (3.0 equiv.), THF, –78°C→rt, o/n, 55–64%; b) KMnO4 (1.5 equiv.), TBAB (1.6

equiv.), CH2Cl2, 0°C→rt, o/n, 61%; c) Pb(OAc)4 (1.1 equiv.), NaHCO3 (7.0 equiv.), 1,2-dichloroethane, 0°C, 30

min; d) TFA (1.1 equiv.), CH2Cl2, 30 min, 94% over two steps (c and d).

Tetracyclic aldehyde 78 was converted into O-silyl protected diene 73 in 95% yield using DBU,

DMAP and TBDPSCl. Extensive investigations into the hetero-Diels–Alder reaction between

diene 73 and formaldehyde were attempted. Diene 73 was exposed to a variety of formaldehyde

sources in the presence of Lewis acid. A combination of monomeric formaldehyde, obtained

using a modified Schlosser method,63

in the presence of dimethylaluminium chloride gave

pentacycle 74 in moderate yield.62

At this stage, whilst attempting to hydrogenate the allylic double bond in silyl ether 74 under

standard conditions only complete desilylation was observed. When carried out immediately

after the hetero-Diels–Alder reaction, this gave allylic alcohol 81 in an improved 66% yield over

Introduction

43

two steps.62

The C16 stereochemistry of alcohol 81 was established by X-ray crystallography and

proved that the dienophile had preferentially attacked from the bottom face of diene 73.

Scheme 23. Synthesis of pentacyclic intermediate 81a with correct C16 stereochemistry.

a) TBDPSC1 (1.5 equiv.), DMAP (0.2 equiv.), DBU (5.0 equiv.), CH2Cl2, 0°C, 1.5h, 95%; b) monomeric-HCHO

(1.5 equiv.), Me2AlCl (3.0 equiv.), THF, 0°C→rt, 3 h; c) H2/Pd/C (10 mol%), NaHCO3 (1.6 equiv.), CHCl3, o/n, 66%

over two steps; d) Na·Np (0.5M in THF; 8.0 equiv.), THF, –78°C, 59%; e) aqueous HCHO (37% in H2O; 50.0

equiv.), NaBH3CN (5.0 equiv.), AcOH (6.0 equiv.), 2.5 h, 98%.

Although detosylation of 81 followed by N4- methylation gave O- alkylated 81a in 58% yield,

elaboration of the E-ring in pentacycle 81 proved difficult.62

The alcohol moiety in 81 proved

unreactive towards standard oxidation conditions such as Dess-Martin periodinane, Swern, PDC,

PCC, TPAP, DDQ, AgCO3, SO3-py and Jones. The double bond proved unreactive to

hydrogenation and isomerisation using rhodium(I) catalyst, RhCl(Ph3P)3. Attempts at radical

isomerisation of the double bond had inverted the stereochemistry of the C16 hydrogen, and as

such another approach towards the final oxygen heterocyclic E-ring was investigated.

Introduction

44

1.6.4 Conjugated iminium approach towards (±)-alstonerine

Following the failure to install the E-ring oxygen heterocycle of (–)-alstonerine via either of the

previously outlined aldol or hetero-Diels–Alder approaches, it became clear that a change in

strategy was required.

A modified approach was envisaged, whereby the hydroxymethyl-C16 substituent of the E-ring

would be incorporated earlier in the sequence. This would be achieved via a directed

nucleophilic ring-opening reaction of hydroxymethyl-aziridine 82.64,65

This strategy-level

transformation would increase the level of convergence in the sequence, by implementing the

entire carbon skeleton of alstonerine from three parent substrates. The three components 62, 82

and 86 would be combined to give cyclisation substrate 84, which contained all of the necessary

carbon atoms required for the carbon skeleton of alstonerine (Figure 14, below).

Figure 14. Retrosynthetic analysis (±)-alstonerine 4.

The synthesis would be completed by combining the tandem tetrahydropyridine–Pictet–Spengler

cyclisation with an intramolecular Michael-type addition. The ambitious triple cyclisation would

be followed by FGI and oxidation level adjustment. The order of ring formation in the tandem

Introduction

45

triple cyclisation would be pivotal to its success. Crucially, tetrahydropyridine 84a must be

formed first (Step a, Figure 15). Michael-type addition must then follow (Step c, Figure 2),

which would allow the Pictet–Spengler cyclisation to take place (Step d, Figure 2).

Figure 15. Lewis acid-catalysed tandem cyclisation of 84 in synthesis of (±)-alstonerine.

From the retrosynthesis (Page 44), it can be seen that this approach required the synthesis of the

new aziridine 82 that already possessed the hydroxymethyl-substituent required for the eventual

C16 position. For the initial work, racemic hydroxymethyl-substituted 82 was synthesised in

favour of the single enantiomer, as racemic 82 could be achieved from commercially available

Z-2-butene-1,4-diol in a relatively short sequence. The synthesis of 82 is discussed later

(Scheme 25, Page 51, Chapter 2).

Introduction

46

Forward Synthesis

When treated with n-BuLi, O-lithiated hydroxymethyl-substituted aziridine 82 was found to

undergo completely regioselective and stereospecific ring-opening with the sulfone-stabilised

carbanion of 1-phenylsulfonyl-3,3-dimethoxypropane 62.67

β-Ketoesterification of the resulting

alcohol 83 using either NaOAc or DMAP as catalyst with diketene gave cyclisation precursor 84

in 54% yield. At this stage, numerous Lewis acidic cyclisation conditions were attempted.66

In all cases, tetrahydropyridine formation was immediately followed by intramolecular

Pictet–Spengler cyclisation to give tetracyclic 87, which prevented the synthesis of the

alstonerine E-ring, as the premature Pictet–Spengler cyclisation removed the required

1,4-conjugation and meant that conjugated iminium intermediate 84b could not be formed.

Scheme 24. Failed Lewis acid-catalysed tandem cyclisation of 84 in the synthesis of alstonerine.

a) 62 (1.5 equiv.) + n-BuLi, THF, –78°C→rt, o/n, 83%; b) Diketene (1.3 equiv.), DMAP (10 mol%), THF, rt, 2 h,

51%; c) TMSI (6.0 equiv.), MeCN, 0°C, 1 h, 86%.

It is important to note that during this approach, nucleophilic ring-opening reactions carried out

on the MOM-protected derivative of aziridine 82 with the sulfone-stabilised anion of 62 showed

Introduction

47

little regioselectivity, and as such the hydroxymethyl-substituent was identified as vital in

directing the approach of the nucleophile.

Results and Discussion

48

Chapter 2

Results &

Discussion


49

Introduction to the final approach

Having discussed previous endeavours towards the total synthesis of alstonerine in Chapter 1, the

focus of this chapter will be to present the final approach, which culminated in an aziridine-based

synthesis of (±)-alstonerine. The final approach relied heavily on the successful aspects of the

Craig group’s previous approaches,67,68

notably the regioselective, stereospecific ring-opening of

hydroxymethyl-substituted aziridine 82 and a reductive modification of the Pictet–Spengler

cyclisation (Retrosynthesis, Figure 16, below). The approach will be discussed in two sections.

Section 2.1 The synthesis of key intermediate α,β-unsaturated lactam alcohol 90

The premature Pictet–Spengler cyclisation of 84d observed by Wildman (Scheme 24, Page 46),66

would be addressed by altering the order in which the E- and C-rings were constructed. We

would ensure that the Pictet–Spengler cyclisation could not occur before the E-ring is

synthesised by synthesising an equivalent intermediate to the tetrahydropyridine 84c used

previously. The new intermediate 90 will contain an α,β-unsaturated lactam ring in-place of the

tetrahydropyridine motif employed previously. This would act as a masked tetrahydropyridine

and would remain unreactive to Pictet–Spengler cyclisation until partial reduction of the lactam

carbonyl group. The E-ring would then be introduced, by stepwise β-ketoesterification of lactam

alcohol 90 and diastereoselective intramolecular Michael addition of the resulting β-ketoester.

The masked tetrahydropyridine lactam–alcohol 90 would be synthesised by directed

ring-opening of hydroxymethyl-substituted aziridine 82, as discussed in the conjugated iminium

approach, but the sulfone nucleophile would contain the orthoester moiety 88, this would allow

access into the lactam-oxidation level of 90.

Section 2.2 Synthesis of Macroline-related alkaloids from lactam–alcohol 90

Following E-ring formation, the second stage of the synthesis would begin with partial reduction

of the lactam carbonyl to unmask tetrahydropyridine 84c and affect the Pictet–Spengler

cyclisation. This would be followed by oxidation level adjustment of the E-ring and FGI to

complete the synthesis of alstonerine. The synthesis of related indole alkaloids will also be

discussed in this section.


50

Figure 16. Retrosynthesis for the final approach (±)-alstonerine 4.


51

2.1 Synthesis of key intermediate α,β-unsaturated lactam–alcohol 90

2.1.1. Synthesis of strategy-level directed aziridine ring-opening reaction substrates

In order to optimise the aziridine ring-opening reaction, we had first to carry out the synthesis of

hydroxymethyl-substituted aziridine 82 and trimethyl 3-(phenylsulfonyl)orthopropionate 88 in a

concise and efficient manner, such that large quantities of each would be readily accessible.

2.1.2. Synthesis of hydroxymethyl-substituted aziridine 82

Previous work within the group by Mathie66

and Tholen57

had established a robust route, by

which hydroxymethyl-substituted aziridine 82 was prepared on multi-gram scale from

Z-2-butene-1,4-diol 92, in an overall yield of 50% over six steps. (Scheme 25)

Scheme 25. Synthesis of hydroxymethyl-substituted aziridine 82.

a) NaH (0.98 equiv.), THF, 0C→rt, 24 h, then TBSCl (0.98 equiv.), rt, 24 h, 98%; b) Chloramine-T (1.2 equiv.),

PTAB (0.1 equiv.), MeCN, rt, 48 h, 76%; c) NaH (4.0 equiv.), THF, 0C→rt 4 h, then cooled to –78C and saturated

aqueous NH4Cl (excess), 94%; d) 1-methylindole (2.0 equiv.), BF3·OEt2 (1.1 equiv.), anhydrous NaHCO3

(4.0 equiv.), CH2Cl2, –78C, 6 h, 87%; e) DIAD (1.5 equiv.), Ph3P (1.2 equiv.), THF, rt, 16 h, 86%; f) TBAF·3H2O

(1.1 equiv.), THF, 0C→rt, 16 h, 95%.

Monoprotection of Z-2-butene-1,4-diol 92 as the TBS silyl ether and subsequent hydroxyl-

assisted aziridination69

afforded syn-configured aziridine 93. Sodium or potassium hydride-

mediated aza-Payne rearrangement of 93 ensued stereospecifically with inversion of

configuration at the C2 carbon via an SN2 type mechanism, to give epoxide 94 in excellent yield.


52

Boron trifluoride etherate-assisted ring-opening of epoxide 94 by N1-methylindole occurred at

the less hindered position to give anti-amino alcohol 95. The syn-aziridine motif in 96 was

reformed using Mitsunobu aziridination conditions.70

O-Silyl deprotection using TBAF

completed the synthesis of the hydroxymethyl-substituted aziridine 82.

2.1.3. Synthesis of sulfone 88

Although Ghosez and co-workers had described the synthesis of trimethyl

3-(phenylsulfonyl)orthopropionate 88 from the methanolysis of the β-sulfonylnitrile derivative of

acrylonitrile,71

the work of Parham

had been used previously within the group.72,73,74

Dichlorocyclopropanation of phenyl vinyl sulfide 97 followed by S-oxidation to sulfone 99 and

basic methanolysis gave orthoester 88 in ~ 50% yield on small scale (Scheme 26).

Scheme 26. Original synthesis of orthoester 88.

a) CCl3CO2Et (1.3 equiv.), NaOMe (1.5 equiv.), Petrol80

, –20C→rt, 18 h, 61% following the method outlined by

Tholen57

; b) H2O2 (4.0 equiv.), HOAc, 100C, 3 h, 90%; c) NaOMe (3.5 equiv.), MeOH, 65C, 3 h, 98%.

Although yields were generally acceptable for the preparation of 88 on a small scale (~2.5 g), the

expense of phenyl vinyl sulfide, duration of the sequence and poor cyclopropanation reaction led

to an investigation into a more practical route for multi-gram synthesis.

Our first step was to find a scalable synthesis of phenyl vinyl sulfide. This was achieved by

following the method of Carr and co-workers, whereby we were able to synthesise a 23 g batch

of phenyl vinyl sulfide 97 in 68% yield from benzenethiol using a one-pot procedure.75

Of the

many reported syntheses of phenyl vinyl sulfide,76,77,78,79

this method was chosen in order to

avoid handling the powerful alkylating agent 1-phenylthio-2-bromoethane 100 and gaseous

halogens (Scheme 27, below).


53

Scheme 27. Scalable synthesis of phenyl vinyl sulfide 97.

a) NaOEt (1.0 equiv.), C2H4Br2 (1.5 equiv.), EtOH, –30C→rt, 30 min, then NaOEt, 95C, 24 h, 68%.

With a scalable route to phenyl vinyl sulfide in hand, optimisation of the

dichlorocyclopropanation reaction would lead to a practical and scalable route to orthoester 88.

2.1.4 Recrystallisation of sulfone 99

The conditions outlined previously for the dichlorocyclopropanation of phenyl vinyl sulfide gave

poor yields of purified 2,2-dichlorocyclopropyl phenyl sulfide 98, due to product degradation

during purification by distillation. To avoid this, the viability of S-oxidising the crude material

obtained from dichlorocyclopropanation of phenyl vinyl sulfide was investigated. We knew that

the resulting 2,2-dichlorocyclopropyl phenyl sulfone 99 was a crystalline solid. Therefore, we

envisaged that upon S-oxidation, sulfone 99 could be separated from residual ethyl methyl

carbonate, (produced from ethyl trichloroacetate during the cyclopropanation) by crystallisation.

Investigations into a suitable solvent system found that a 2:1 petrol:ethanol solvent system

allowed recovery of 2,2-dichlorocyclopropyl phenyl sulfone 99 from a mixture containing 50%

ethyl methyl carbonate. Critically, S-oxidation of phenyl vinyl sulfide remaining from the

dichlorocyclopropanation step resulted in phenyl vinyl sulfone, which could not be separated

from the desired product via recrystallisation. Thus, in order purify 2,2-dichlorocyclopropyl

phenyl sulfone 99 by recrystallisation on large scale, the dichlorocyclopropanation reaction

required optimisation.


54

2.1.5 Optimisation of dichlorocyclopropanation synthesis of 98

Initial attempts using petrol distilled from calcium hydride and ethyl trichloroacetate as supplied

from the manufacturer showed no conversion (Entry 1, Table 1). We suspected that this complete

lack of reactivity was due to a competitive reaction between any olefinic impurities in the petrol

and the reactive intermediate dichlorocarbene (Entry 2, Table 1). With this in mind, ethyl

trichloroacetate was added at a rate of 6.0 mL min–1

to a solution of 97 and excess NaOMe in

olefin free petrol80

at –20C. After warming to room temperature overnight and work-up,

1H NMR analysis showed complete consumption of starting material (Entry 3, Table 1).

Although these conditions were viable for small-scale synthesis, the difficulties involved in

removing olefin impurities by washing litres of petrol with concentrated sulfuric acid and

KMnO4 led to the search for an alternative solvent for large scale synthesis. Concurrent

dichlorocyclopropanation reactions were run in toluene, cyclohexane and CH2Cl2 at 0C (Entries

4, 5 and 6 respectively, Table 1). Analysis by TLC after 1 h showed that the rate of reaction was

hugely increased in CH2Cl2, reaching completion after 1 h (Entry 6, Table 1). The reaction

temperature was decreased to −78C, and the addition of ethyltrichloroacetate carried out

dropwise via dropping funnel on large scale (Entry 7, Table 1). This eliminated the potentially

dangerous temperature spike that was observed during small-scale reactions.


55

Table 1. Dichlorocyclopropanation of phenyl vinyl sulfide.

Entry Conditions Time Temp.

Conversion%

1 CCl3CO2Et (1.3 equiv.),a

NaOMe (1.5 equiv.), Petrolb

24 h −20C 0


NaOMe (1.5 equiv.), Petrolc

24 h −20C 50 − 60

3 CCl3CO2Et (1.3 equiv.),d

NaOMe (1.5 equiv.), Petrolc

24 h −20C 90


NaOMe (1.5 equiv.), PhMe 24 h 0C ~ 60


NaOMe (1.5 equiv.), C6H12 24 h 0C 0


NaOMe (1.5 equiv.), CH2Cl2 1 h 0C 100


NaOMe (1.5 equiv.), CH2Cl2 4 h −78 → 0C 100

a ethyl trichloroacetate added in one portion dropwise;

b petrol distilled over CaH2;

c olefin free petrol

80;

d ethyl

trichloroacetate added at rate of 6.0 mL min–1

.

S-Oxidation of crude dichlorocyclopropane 98 obtained using CH2Cl2 (Entry 7, Table 1), was

achieved using peracetic acid generated in situ from acetic acid and hydrogen peroxide.

Recrystallisation from 2:1 petrol:ethanol yielded 2,2-dichlorocyclopropyl phenyl sulfone 98 in

>90% over two steps.

2,2-Dichlorocyclopropyl phenyl sulfone 99 was converted into trimethyl 3-

(phenylsulfonyl)orthopropionate 88 in 98% yield, by treating 99 with sodium methoxide in

anhydrous methanol under reflux for 3 hours. Even trace acidic impurities remaining from the S-

oxidation, led to complete hydrolysis and gave methyl-3-(phenylsulfonyl)propionate 101 in


56

quantitative yield. In order to avoid the formation of 101 during large scale production of sulfone

88, dichlorocyclopropane 98 was purified by chromatography prior to methanolysis.

Scheme 28. Scalable synthesis of orthoester 88.

a) CCl3CO2Et (1.5 equiv.), NaOMe (2.0 equiv.), CH2Cl2, –78C→rt, 6 h; b) H2O2 (4.0 equiv.), HOAc, 100C, 4 h,

91% over two steps; c) NaOMe (3.5 equiv.), MeOH, 65C, 3 h, 98%.


57

2.1.6 Initial work towards the synthesis of key intermediate lactam–alcohol 90

Initial investigations were based on the synthesis of methyl ester 102, as outlined previously by

Tholen.81,57

Treatment of lithiated sulfone 88 with O-lithiated

hydroxymethyl-substituted aziridine 82, followed by mildly acidic work-up, reportedly gave

methyl ester 89 as a single diastereoisomer. However, during initial investigations into moving

from milligram test reactions to multigram synthesis, methyl ester 89 proved difficult to isolate.

Scheme 29. Original four step synthesis of α,β-unsaturated lactam–alcohol 90.

a) n-BuLi (4.1 equiv.), sulfone 88 (2.5 equiv.), THF, –40°C→rt overnight, then 10% citric acid, typically <30%;

b) TBSCl (1.5 equiv.), imidazole (1.5 equiv.), DMAP (0.1 equiv.), DMF, rt, 3 h, 49%; c) 2M TMA (1.1 equiv.),

toluene, rt, 30 min, then 80°C, 3 h, 49%; d) AcOH:H2O:THF, rt, 30 h, 65%.

Although it was believed that the acidic orthoester hydrolysis conditions were responsible for the

capricious nature and low yield of the aziridine ring-opening reaction, it was decided that the

possibility of side reactions/starting material degradation should also be eliminated. To achieve

this, basic stability/mechanistic studies were carried out on both sulfone 88 and

hydroxymethyl-substituted aziridine 82, and the reactivity of aziridine 82 towards nucleophilic

ring-opening was confirmed by reaction with lithiated methyl phenyl sulfone.


58

2.1.7 Substrate stability and mechanistic investigation

We envisaged that degradation of starting materials could be contributing to the low yields

observed for the ring-opening reaction. We also hoped to provide evidence to support our claim

that ring-opening occurs via directed addition of the sulfone nucleophile to

hydroxymethyl substituted aziridine 82a (Path A, Figure A, below), rather than the possible

alternative, whereby an aza-Payne rearrangement occurs, followed by addition to the resulting

epoxide 106 (Path B, Figure 17).

Figure 17. Plausible mechanisms for nucleophilic ring-opening of 82.

In order to probe its reactivity towards aza-Payne rearrangement, hydroxymethyl-aziridine 82

was treated with excess n-BuLi in various solvents, and the reaction followed by NMR over a

prolonged time period. For reference, the suspected aza-Payne by-product 106 was first

synthesised by treating hydroxymethyl-aziridine 82 with NaH in THF at 0°C (for experimental

procedure, see Page 137). This gave epoxide 106 in 77% yield.

To solutions of hydroxymethyl-aziridine 82 in THF, toluene and DME at

–78°C was added n-BuLi. Small aliquots of reaction mixture were then taken at varying

temperatures, subjected to identical aqueous work-up and analysed by 1H NMR. (Figure 18,


59

below) The spectra were then compared to that of epoxide 106. 1H NMR analysis (Figure 18)

provided evidence that hydroxymethyl substituted aziridine 82 does not undergo aza-Payne

rearrangement in THF at temperatures below –30°C. The formation of the new doublet of

doublets at 4.26 ppm in the DME and toluene reactions can be assigned to the product of

aziridine ring-opening by water, due to trace amounts in the solvent or upon work-up.

Figure 18. 1H NMR analysis after 3 h at –30°C showing no aza-Payne rearrangement of 82.

2.1.8 Sulfone stability

We also needed to assess the stability of lithiated sulfone 88 to hydrolysis under our reaction

conditions. The suspected by-product was again synthesised for reference. Sulfonyl orthoester 88

was stirred in HCl:THF solution for 16 hours, yielding methyl ester 101 in 97% yield. No ring-

opening products were observed when ester 101 was reacted with aziridine 82 under standard

ring-opening conditions.


60

Scheme 30. Synthesis of suspected sulfone by-product 101 and attempted ring-opening of 82.

a) aqueous 2M HCl (5.0 equiv.), THF, rt, 1 h, 97%; b) Standard aziridine ring-opening conditions.

To assess the extent of orthoester hydrolysis occurring during the ring-opening reaction, n-BuLi

was added to solutions of sulfonyl orthoester 88 in THF, toluene and DME at –78°C. The

reaction mixtures were allowed to warm slowly from –78°C to room temperature over a period

of 24 hours, and small aliquots were again taken at varying temperatures, subjected to identical

aqueous work-up and 1H NMR (Figure 19, below).

Figure 19. 1H NMR analysis after 3 h at –35°C showing orthoester hydrolysis of 88.


61

Analysis by 1

H NMR showed no trace of orthoester hydrolysis after 3 hours at –35°C in THF.

Both reactions in toluene and DME showed considerable hydrolysis at this temperature. The

reactions were allowed to warm slowly from –35°C to room temperature overnight. Following

work-up and NMR, the spectra of the THF reaction showed negligible formation of methyl ester

101. This provided evidence that orthoester hydrolysis was not responsible for the poor reaction

yield.

2.1.9 Aziridine 81 reactivity towards sulfone nucleophiles

Having demonstrated that neither of our ring-opening reactants 82 or 88 was being consumed by

side-reactions, and provided evidence to support the hydroxymethyl-directed aziridine

ring-opening mechanistic hypothesis, it remained to confirm the reactivity of O-lithio

hydroxymethyl-substituted aziridine 82 towards ring-opening. This was achieved by reacting

O-lithio hydroxymethyl-substituted aziridine 82 with an analogue of the sulfone nucleophile. The

lithio anion of phenyl methyl sulfone 105 was chosen as a model nucleophile. Importantly, 105

had previously been shown to undergo regio- and stereoselective ring-opening reactions with

aziridines by the Craig group.52

The combination of lithiated phenyl methyl sulfone 105 with the

O-lithiated 82 and work-up with 10% aqueous citric acid effected stereospecific and completely

regioselective aziridine ring-opening. Sulfonamidoalcohol 107 was isolated in 73% yield as a

single diastereomer.

Scheme 31. Ring-opening reaction of hydroxymethyl-substituted aziridine 82 with model

nucleophile 105.

a) n-BuLi (2.5 equiv.), MeSO2Ph 105 (2.0 equiv.), THF, –40°C, 2 h, then 10% aqueous citric acid, 73%.


62

2.1.10 Orthoester hydrolysis in the synthesis of 89

Having proven aziridine 82 was a suitably reactive electrophile and stable to degradation under

the reaction conditions, and that sulfone 88 was not being consumed by side-reactions, our

attention turned to evaluating the conditions required for the hydrolysis of the orthoester moiety

in the ring-opened product 108.

Figure 20. Problematic acid-induced hydrolysis of orthoester 108.

Unfortunately, forming the desired methyl ester 89 proved less straightforward than expected.

Initial attempts showed that use of excess saturated aqueous NH4Cl to quench the ring-opening

reaction (Entries 1 and 2, Table 2, below) provided an insufficiently acidic medium to effect

hydrolysis of the orthoester moiety. Switching to aqueous 10% citric acid provided complex

mixtures of products 89 and 108 (Entry 3, Table 2), without complete orthoester hydrolysis.

Increasing the acidity by using saturated aqueous citric acid solution, gave mixtures of 109 and

89 (Entries 4–6, Table 2), but importantly no 108 meaning that complete hydrolysis had

occurred. The next attempt used concentrated aqueous HCl solution and gave α,β-unsaturated

δ-lactone 110 as the single product in good yield (Entry 8, Table 2). The use of 2M aqueous HCl

solution also gave complete hydrolysis, giving lactones 109 as a mixture of sulfone epimers in

good yield (Entry 7, Table 2). Attempts using acetic acid and TFA also failed to give 89 in

reliable yield, and as such an alternative to the ring-opening of 82 was investigated.


63

Table 2. Hydroxymethyl-substituted aziridine 82 ring-opening optimisation.

Entry a) Conditions Ratio

Yield%

1 88 (1.5 equiv.), n-BuLi (2.5 equiv.), –78°C → rt overnight,

saturated NH4Cla

3 : 1

(108:89)

78


saturated NH4Clb

10 : 1

(108:89)

83


10% citric acidb

3 : 1

(108:89)

73


saturated citric acidb

2:1

(109:89)

72

5 88 (2.0 equiv.), n-BuLi (3.0 equiv.)c, –78°C → rt overnight,


1:1

(109:89)

80



3:1

(89:109)

63

7 88 (1.5 equiv.), n-BuLi (2.8 equiv.), –78°C → rt overnight, 2M

aqueous HClb

109 80


concentrated aqueous HClb

110 85d

a Base washed silica used for chromatography b silica used as supplied c concentrated n-BuLi used d yield estimated from crude

1H NMR


64

In order to confirm that the ring-opening reaction was occurring with complete regioselectivity

for the aziridine carbon atom proximal to the hydroxymethyl moiety, the structures of sulfones

109a and 109b were established by X-ray crystallography (Figures 21 and 22, below).

Pleasingly, the structures show that the ring-opening occurred with clean inversion of the

aziridine carbon atom under attack, and illustrates the anti-relationship of the indolymethyl- and

hydroxymethyl-substitutents (labelled C(12) and C(13) respectively, below).

Figure 21. The molecular structure of 109a.

Figure 22. The molecular structure of 109b.


65

2.1.11 O-TBS protected aziridine 96 ring-opening strategy

With the unwanted lactonisation proving persistent, the possibility of using O-silyl protected

hydroxymethyl-substituted aziridine 96 in the ring-opening reaction was briefly revisited.

Previous work within the Craig group had found that when MOM-protected,67

the

regioselectivity of ring-opening reactions of hydroxymethyl-substituted aziridine 82 by the

lithioanion of 1-phenylsulfonyl-3,3-dimethoxypropane 62 was severely eroded.

We rationalised that although O-silylation of hydroxymethyl-aziridine 82 was likely to decrease

the regioselectivity of the ring-opening reaction, lactonisation of the resulting product 102 would

be avoided. This would lead to a robust route to intermediate 90, without altering the overall

number of steps in the synthesis. Importantly, the regioisomers 111 must be separable. Lactam

formation would give 104, which would be deprotected to give α,β-unsaturated lactam–alcohol

90.

Figure 23. Route to α,β-unsaturated lactam–alcohol 90 via O-TBS hydroxymethyl-substituted

aziridine 96.


66

O-TBS protected hydroxymethyl-substituted aziridine 96 was treated with a solution of lithiated

trimethyl 3-(phenylsulfonyl)orthopropionate 88 at –78°C for 2 hours. Work-up with 2M aqueous

HCl and chromatography gave a mixture of epimeric regioisomers

(~15:10:6:5 102a:111a:111b:102b) in good yield. This equated to a synthesis of O-TBS ring-

opened regioisomer 102 in approximately 41% yield as a 3:1 mixture of sulfone epimers

(Scheme 32, below).

Scheme 32. Ring-opening reaction of O-TBS hydroxymethyl-substituted aziridine 96.

a) n-BuLi (2.0 equiv.), sulfone 88 (1.8 equiv.), THF, –78°C→rt o/n, then aqueous 2M HCl, 41%.

Although this route provided a reliable route to O-TBS-protected sulfonamidoalcohol 102, the

loss of regioselectivity in the ring-opening reaction was unacceptable for the final synthesis. The

ring-opening of O-TBS 96, did however provide us with significantly improved quantities of

102. This allowed us to attempt the synthesis of the D- and E-rings, as well as providing material

with which to investigate alternative routes to key intermediate lactam–alcohol 90 that did not

require the need for O-silylation prior to lactamisation. In order to investigate these alternatives,

we first required reliable desilylation conditions to convert O-TBS 102a and 102b into the target

of the on-going aziridine ring-opening optimisation, sulfonamidoalcohol 89.


67

2.1.12 Deprotection of ring-opening product 102

With a route to larger quantities of O-TBS protected ester intermediate 102 established via ring-

opening of O-TBS hydroxymethyl-substituted aziridine 96, and with a view to removing the

need for O-TBS protection prior to lactamisation from the eventual synthesis, we decided to

investigate the selectivity of Lewis acid-catalysed cyclisation of intermediate 112

(Figure 24, below). For these investigations, the cyclisation precursor 112 would be synthesised

by deprotecting O-TBS ring-opening product 102 and subsequent β-ketoesterification of

sulfonamidoalcohol 89.

Figure 24. Route to β-ketoester lactam 113 via selective cyclisation of 112.

We initially attempted a one-pot simultaneous aziridine ring-opening of 96 and O-silyl

deprotection by quenching with 10% HCl in MeOH. However, this proved unsuccessful and led

to further investigations into conditions for the silyl deprotection of O-TBS 102. Standard

fluoride conditions were used for our initial attempts, but both TBAF82

and HF-pyridine83

gave

trans-α,β-unsaturated ester 114 in 76 and 68% yields respectively. Therefore, alternative acidic


68

conditions84

were attempted. This would avoid the unwanted elimination reaction that occurred

rapidly in the presence of basic fluoride. When O-TBS 102 was stirred in a 1% HCl:EtOH

solution, clean deprotection was observed, but acid-catalysed transesterification gave the ethyl

ester derivative of 89 in quantitative yield. When repeated with a solution of 1% HCl:MeOH

followed by neutralisation with solid NaHCO3, filtration and concentration, deprotected methyl

ester 89 was obtained in 63% yield. By decreasing the concentration to 0.01M and increasing the

reaction time, complete conversion was observed by TLC analysis, although the low yield

remained. Investigations into the method of quenching the reaction led to an increased yield of

98% when NH3 in MeOH was used (Table 3).

Table 3. Silyl ether 102 deprotection

Entry a) Conditions Ratio

Yield%

1 TBAF·3H2O (1.1 eq.), THF, 0°C, 15 min 114 76

2 HF·pyridine (1.1 eq.), THF, 0°C, 2 h 114 68

3 1% HCl in MeOH, 0.1M, rt, 6 h, aqueous NaHCO3 (mg scale) 89 93

4 1% HCl in MeOH, 0.01M, rt, 16 h, aqueous NaHCO3(>100 mg

scale)

5:1

89:114

88

5 1% HCl in MeOH, 0.01M, rt, 16 h, then NH3 in MeOH, –78°C, 15

min

89 98

6 1% HCl in MeOH, 0.01M, rt, 16 h, MgSO4 89 67


69

2.1.13 Esterification of sulfonamidoalcohol 89 and subsequent TMA mediated cyclisation

The next stage of this approach was to synthesise the carbon skeletons of the D- and

E-ring. As shown previously (Scheme 29, Page 57), ring-opened protected alcohol 102 was

converted into α,β-unsaturated lactam–alcohol 90 (Scheme 33, below). Although this route

provided lactam–alcohol 90 which contained the core of the D-ring, the lactamisation suffered

from a competing facile sulfone elimination reaction, as highlighted previously

(Table 3, Page 68), which gave an inseparable mixture of O-TBS lactam 104 and eliminated

O-TBS-trans-α,β-unsaturated ester 104a. The unwanted trans-ester 104a could be separated

from the desired lactam–alcohol following O-TBS deprotection (Scheme 33, below). Attempts to

effect cyclisation of the trans-α,β-unsaturated ester 114 failed under prolonged thermal and

microwave conditions, due to its rigid geometry (Scheme 33, below).

Scheme 33. Original route to lactam–alcohol 90 and facile sulfone elimination of O-TBS 102.

a) 2M TMA (1.1 equiv.), toluene, rt, 30 min, then 100°C, 3 h, 69%; b) AcOH:H2O:THF, rt, 30 h, 65%.

With sulfonamidoalcohol 89 in hand as shown in the previous section (Table 3, Page 68), our

attentions turned to removing the two protecting group steps by instead converting

sulfonamidoalcohol 89 into the corresponding β-ketoester 112. Both Wildman66

and Tholen57

had carried out similar transformations previously within the group, using either diketene or 4H-


70

2,2,6-trimethyl-1,3-dioxin-4-one. For the β-ketoesterification of 89 we chose the latter

conditions, as we feared that the base-required in the diketene reaction would bring about the

corresponding trans-α,β-unsaturated ester 112a via the aforementioned facile sulfone

elimination. Under thermal conditions (Entries 1–4, Table 4, below), only moderate yields of 112

were obtained as the prolonged reflux led to formation of trans-112a.85

Decreasing the

temperature to 90°C failed to improve the yield of 112, however heating alcohol 89 with

4H-2,2,6-trimethyl-1,3-dioxin-4-one 115 under microwave conditions significantly increased the

yield of 112 (Entries 5–7, Table 4). Decreasing the duration of the microwave reaction provided

112 in 76% yield, with only trace amounts of 112a (Entry 8, Table 4).

Table 4. β-ketoesterification of 89.

Entry a) Conditions Time Temp.

Ratio 112:112a Yield 112

1 115 (1.1 equiv.), toluene 24 h a 110C 3:1 ~ 30 – 50%

2 115 (2.0 equiv.), toluene 24 h a 110C 3:1 ~ 30 – 50%

3 115 (2.0 equiv.), toluene 2 h a 110C 2:1 58%

4 115 (1.5 equiv.), toluene 24 h a 90C 4:1 35%

5 115 (1.5 equiv.), toluene 30 min b 150C >90:1 75%

6 115 (1.5 equiv.), toluene 30 min b 130C trace 112a 69%

7 115 (1.5 equiv.), toluene 30 min b 120C trace 112a 68%

8 115 (1.5 equiv.), toluene 30 min b 150C

trace 112a 76%

a Standard heating under reflux b Microwave heating in sealed tube

Having established conditions for the synthesis of β-ketoester 112, the cyclisation to

α,β-unsaturated lactam β-ketoester 113 was attempted using the previously established


71

trimethylaluminium conditions. β-Ketoester 112 was converted into 113 via Lewis acid-

catalysed lactamisation in 26% yield when using 2.0 equivalents of TMA. The reaction was

selective in forming the desired N4–C3 linked 113 over the possible N4–C21 linked amide,

however significant amounts of the corresponding trans-α,β-unsaturated ester were also formed,

which was inseparable from the product. The yield of 113 was increased to 61% by decreasing

the amount of TMA to 1.1 equivalents, but due to the persistence of the facile sulfone

elimination, which persisted throughout the deprotection, β-ketoesterification and lactamisation

steps of this approach, an alternative approach to the synthesis of the D-ring in lactam 113 was

sought.

Scheme 34. Synthesis of the D-ring via lactamisation of β-ketoester 112.

a) TMA (1.1 equiv.), toluene, 100°C, 1 h, saturated aqueous Rochelle salt, 26–61%.


72

2.1.14 Final synthesis of α,β-unsaturated lactam–alcohol 90

At this stage, the synthesis of key intermediate α,β-unsaturated lactam–alcohol 90 via

ring-opening hydroxymethyl-aziridine 82 had been hampered by lactone formation that gave

almost exclusively lactones 109a and 109b, instead of the desired methyl ester 89.

The most reliable route to lactam–alcohol 90 had been via the ring-opening reaction of O-TBS

protected aziridine 96. This reaction had shown complete consumption of aziridine starting

material; however the regioselectivity had suffered to such an extent that its use was not viable in

the final route to alstonerine. Sulfone elimination during both the attempted deprotection of

O-TBS ring opened intermediate 102 and D-ring-forming lactamisaton of O-TBS 102 or

β-ketoester 113 had led to significant amounts of the corresponding trans-α,β-unsaturated methyl

esters, whose geometry prevented lactam formation. As such, attention was focused on using

lactones 109a and 109b as intermediates in our synthesis. This decision had a huge impact on the

final approach to alstonerine.

The possibility of Lewis acid mediated intramolecular O- → N-transacylation was investigated.

We considered that subjecting lactone 110 to modified Friedel–Crafts type conditions may give

rise to reactive acylium intermediate 116; Subsequent cyclisation should favour the more

thermodynamically stable lactam 90.

Figure 25. Lewis acid mediated intramolecular O- → N-transacylation.

α,β-Unsaturated lactone 110 was chosen as the substrate for initial experiments. We rationalised

that treatment with oxaphilic trimethylaluminium would form acylium intermediate 116. We

hoped that the cis-geometry of the starting lactone 110 would be transferred to intermediate 116


73

and that this may increase the rate of lactamisation. When 1.1 equivalents of Lewis acidic

trimethyl aluminium in solution was added to α,β-unsaturated lactone 110 in toluene at room

temperature, then heated at 100°C for 1 hour, complete O- to N-transacylation was observed and

α,β-unsaturated lactam–alcohol 90 was isolated in excellent yield.

Scheme 35. Synthesis of 90 by intramolecular O- → N-transacylation.

a) TMA (1.1 equiv.), toluene, rt, 1 h, then 100°C, 15 min, 91%.

We hoped to repeat this intramolecular transacylation lactamisation on sulfone-containing

lactones 109a and 109b. This would provide the lactam oxidation level analogue of the

previously discussed tetrahydropyridine intermediate 118, and subsequent sulfone elimination

would give α,β-unsaturated lactam–alcohol 90. We also rationalised that were sulfone

elimination to occur prior to O- to N-transacylation, then α,β-unsaturated lactone 110 would be

formed, whose cis-geometry would allow cyclisation.


74

Scheme 36. Synthesis of α,β-unsaturated lactam 90 via intramolecular lactamisation–elimination.

a) TMA (1.5 equiv.), toluene, 120°C, 2 h, saturated aqueous Rochelle salt, 97%; b) TMA (1.1 equiv.), toluene, 0°C,

1 h, saturated aqueous, NH4Cl, 73%.

That O- → N-acyl transfer preceded elimination was indicated by the isolation of δ-lactam 118 in

good yield when lactone 109a was exposed to trimethylaluminium at 0°C. The structure of 118

was confirmed by X-ray crystallography. Importantly, the anti-relationship between the

indolylmethy- and hydroxymethyl substituents of 118 can clearly be seen (Figure 26, below).

Sulfonyllactam 118 was converted into α,β-unsaturated lactam 90 by resubmission to the

trimethylaluminium reaction conditions. When applied to the large scale synthesis, we were able

to reliably synthesis multigram batches of α,β-unsaturated lactam 90 in just two steps from

hydroxymethyl-substituted aziridine 82 (Scheme 37, below). In addition, by isolating lactones

109 from the ring-opening reaction of 82 and subsequently carrying out an O- to N-

transacylation, we had removed the tedious and labour intensive protection and deprotection

steps from our total synthesis.


75

Scheme 37. Optimised route to α,β-unsaturated lactam 90.

a) Sulfone 88 (1.5 equiv.), n-BuLi (2.8 equiv.), THF, –78°C→rt o/n, then aqueous 2M HCl, 80%; b) TMA (1.5

equiv.), toluene, 120°C, 2 h, saturated aqueous Rochelle salt, 94%.

Figure 26. Molecular structure of δ-lactam intermediate 118.


76

2.2 Synthesis of Macroline-related alkaloids from lactam–alcohol 90

2.2.1 Synthesis of lactam–lactone 91

We now aimed to use lactam–alcohol 90, in the total synthesis of (±)-alstonerine. Previous

attempts to construct the pentacyclic core of alstonerine 85 via an iminium ion-initiated cascade-

style reaction had failed (Scheme 24, Page 46), as the facile Pictet–Spengler cyclisation had

occurred prior to E-ring formation.66

This had led to tetracycle 87, from which point the E-ring

could not be incorporated. Therefore an alternative approach, whereby the E-ring fragment was

installed prior to the Pictet–Spengler cyclisation using stepwise

β-ketoesterification and intermolecular Michael addition had been investigated by Tholen

(Scheme 38).57

Our current approach retained the idea of building the E-ring prior to Pictet–

Spengler cyclisation, due in part to the facile nature of the DBU-catalysed cyclisation, but more

significantly, because we were aware of possible Michael-type indole addition (see below).

Scheme 38. Initial synthesis of pentacyclic lactone 85.

a) Diketene (1.3 equiv.), KOAc (0.1 equiv.), THF, 70°C, 1.25 h, 78%; b) DBU (0.2 equiv.), THF, rt, 3 h, 83%;

c) DIBAL (1.1 equiv.), THF, –78 C, then TFA (0.1 equiv.), 78%.

Due to supply problems, an alternative reagent to diketene was investigated for the

β-ketoesterification of lactam–alcohol 90. During earlier studies towards the synthesis of the

D-ring via β-ketoesterification of the aziridine ring-opening product (Table 4, Page 70), we

found that β-ketoesterification occurred cleanly under microwave heating with

4H-2,2,6-trimethyl-1,3-dioxin-4-one. Multi-gram quantities of β-ketoester 113 were reliably

made using this process. On larger scales, we found that an increase from sub-stoichiometric


77

base to 2.0 equivalents of DBU was required to convert β-ketoester 113 into tetracyclic 91 in

comparable yields to those reported for small-scale reactions.57

Scheme 39. Optimised, scalable synthesis of key intermediate lactam–lactone 91.

a) 4H-2,2,6-trimethyl-1,3-dioxin-4-one (1.5 equiv.), toluene, 150°C µW, 20 min, 97%; b) DBU (2.0 equiv.), THF,

rt, 12 h, 93%.

Having established a reliable and scalable synthesis of lactam–lactone 91, our attentions turned

to completing the assembly of the azabicyclo[3.3.1]nonane core motif via Pictet–Spengler

cyclisation.


78

2.2.2 Synthesis of pentacyclic lactone 85 via C-ring forming Pictet–Spengler cyclisation

Previous investigations within the Craig group,57,66–68

as well as significant precedent from

Cook3,8,9

and Bailey,3 had shown that treatment of the hemiaminal derivative of lactam–lactone

91 with either Lewis or Brønsted acid facilitated the required stereospecific intramolecular

Pictet–Spengler cyclisation. This formed the C2–C3 bond and provided the azabicyclic core

motif as a single diastereomer.

Initially, we attempted to isolate hemiaminal 119 in order to investigate its reactivity towards

Brønsted acids of varying pKa (Scheme 40, below). The C3 carbonyl was partially reduced by

treating lactam–lactone 91 with a stoichiometric quantity of DIBAL. Non-acidic work-up gave

hemiaminal 119 in reasonable yield, which proved to be stable to saturated aqueous NH4Cl and

silica gel. For the iminium ion formation and subsequent cyclisation, sub-stoichiometric

quantities of TFA were sufficiently acidic to effect the conversion of purified hemiaminal 119

into pentacyclic lactone 85 in 91% yield.

Scheme 40. Interrupted Pictet–Spengler cyclisation of 91.

a) DIBAL (1.5 equiv.), THF, –78C, 1 h then wet EtOAc and saturated Rochelle salt, –78C→rt, overnight, 51%;

b) TFA (0.1 equiv.), THF, –78C, 2 h, 91%.

However, when attempting to combine the partial reduction and Pictet–Spengler cyclisation in a

single step by quenching the DIBAL reaction with strong acid, the use of TFA gave negligible

cyclised pentacycle 85, instead yielding a complex mixture of reduced products (Scheme 41,

below). Whilst it was rationalised that hemiaminal 119 and tetrahydropyridine 84c were a result

of using insufficiently acidic conditions to quench the reaction, we were keen to establish the

origin of unexpected tetrahydropyridine 120.


79

Scheme 41. Initial by-products from Pictet–Spengler cyclisation of 91.

a) DIBAL (1.2 equiv), THF, –78C, 2 h then wet EtOAc and TFA (1.0 equiv.), THF, –78 C→rt, 30 min, (~3:2:2:1

119:84c:85:120), 80%.

The cleavage of an N-Bn-protected indole residue whilst attempting the triethylsilane-mediated

indole reduction of 121 was reported by Guo (Scheme 42).86

Although the mechanism for the

disconnection of the indole unit was stated as being unclear, we believed that a similar mode of

action was leading to our by-product 120. It was rationalised that under acidic conditions,

iminium ion 121a was produced by thermodynamic protonation of the indole substituent. This

was subsequently intercepted in an SN2’ type 1,4-manner by hydride.

Scheme 42. Loss of indole moiety in 121.

a) Et3SiH (20.0 equiv.), TFA (excess), CH2Cl2, rt, 94%.


80

In our case, intermediate iminium 123 (Scheme 43, below) was intercepted by ethanol in a

similar fashion to that seen by Guo. The ethanol resulted from quenching the DIBAL reduction

reaction with ethyl acetate. Thus we hoped to avoid the formation of 123 by switching from wet

ethyl acetate to non-nucleophilic wet diethyl ether to quench the DIBAL reaction.

Scheme 43. Mechanism for loss of indole moiety via 123 and optimised synthesis of pentacyclic

lactone 85.

a) DIBAL (1.2 equiv.), THF, –78C, 2 h then wet EtOAc and TFA (1.0 equiv.), THF, –78C→rt, 30 min, 19% 84c;

b) Triflic acid (0.1 equiv.), THF, –78C, 1 h, 100%; c) DIBAL (2.0 equiv.), THF, –78C, 3 h then wet Et2O and

triflic acid (1.0 equiv.), THF, –78C→rt, 30 min, 91%.

As tetrahydropyridine 84c was similar to Wildman’s intermediate (Scheme 24, Page 46), we

rationalised that treatment with a strong acid would lead to rapid Pictet–Spengler cyclisation. In

practice, treating tetrahydropyridine 84c with sub-stoichiometric quantities of triflic acid gave


81

pentacyclic lactone 85 in quantitative yield. When the wet diethyl ether quench followed by

triflic acid mediated Pictet–Spengler cyclisation conditions were applied to the DIBAL reduction

of lactam–lactone 91, pentacyclic lactone 85 was isolated in excellent yield as the sole product

(c, Scheme 43, above). Although alternative conditions were attempted for the quench of the

DIBAL reduction, both 2.0 M and concentrated HCl, acetic acid and TFA all gave mixtures of

aminal 119, tetrahydropyridine 84c and pentacycle 85, with only triflic acid providing 85 cleanly

and in 91%.


82

2.2.3 Attempts at N4-and O-functionalisation of 91

Having successfully synthesised pentacyclic lactone 85 our attention turned to adjusting the

oxidation level of the E-ring. Our initial aim was to N4-and O-functionalise lactam–lactone 91, so

a one-pot C3 and C21 carbonyl reduction combined with acid-mediated Pictet–Spengler

cyclisation and lactol elimination could be accomplished. This would pave the way to complete

the total synthesis (Figure 27).

Figure 27. Proposed completion of alstonerine via Pictet–Spengler of N4-and O-methylated 124.

Our investigations began with the synthesis of both N4-and O-methylated lactam–lactone 124.

The N4-desulfonylation was completed as previously, by treating N4-tosyl lactam–lactone 91

with 8.0 equivalents of sodium naphthalenide at –78°C.87

This provided the free amine in good

yield. For the N- and O-methylation, we hoped that treatment of 2.0 equivalents of base,

followed by excess iodomethane would provide bis-methylated 124. However in practice,

treating 125 with either lithium or sodium bases gave no reaction (Entries 1 and 2, Table 5,

below), due to the stability of the metalated enol intermediate. A switch to potassium

bis(trimethylsilyl)amide (Entries 3–6, Table 5) provided a more reactive potassium enolate and

led to the formation of mono-methylated 126b and bis-methylated 126a. Analysis by HMBC and

NOESY NMR showed that C-methylation had been favoured under these conditions. That

C-methylation was favoured over N4-functionalisation was shown by isolation of

mono-methylated 126b, and despite increasing reaction duration and equivalents of both base

and methylating agent, complete conversion to bis-methylated 126a was never achieved.


83

Table 5. Attempted N4-and O-methylation of lactam–lactone 124.

a) Na·Np (8.0 equiv.), THF, –78C, 2 h, sat. aq. NH4Cl, 99%; b) See Table 5.

Entry b) Conditions Tim

e

Ratio

126a:126b

Yield%

1 n-BuLi (2.0 equiv.), MeI (2.1 equiv.), –78C→rt 16h - -

2 NaH (3.0 equiv.), MeI (2.8 equiv.), 0C 16 h - -

3 KHMDS (2.5 equiv.), MeI (3.0 equiv.), 0C 16 h 2:3 56

4 KHMDS (2.5 equiv.), MeI (3.0 equiv.), 0C 74 h 1:3 68

5 KHMDS (2.5 equiv.), MeI (3.0 equiv.), –78C 74 h 1:3 68

6 KHMDS (1.2 equiv.), MeI (1.1 equiv.),

–78C→rt 74 h 3:2 93

Having failed to synthesise O- and N-methylated Pictet–Spengler precursor 124 due to

preferential C- rather than O-alkylation and low amine nucleophilicity, we decided to investigate

the individual steps of the desired deprotection–reduction process. We rationalised that

desulfonylation of pentacyclic lactone 85 would provide a secondary amine that should be highly

reactive to N4-methylation. For the reduction of the E-ring, we rationalised that

O-silylation would occur preferentially to C-silylation, which would provide us with a substrate

for final reduction of the E-ring. For the detosylation, sodium naphthalenide conditions were

again used;87

these gave the free N4-H amine 127 in 92% yield. Analysis by 1H NMR showed

that approximately 60% of the resulting compound existed as the zwitterion in CDCl3. However,

when treated with the methylating conditions used in the synthesis of alstonerinal, amine 127

proved resistant to alkylation (Entry 3, Table 6, below). Starting amine was also recovered using


84

reductive amination and strongly basic conditions (Entries 1 and 2, Table 6) leading us to attempt

the O-functionalisation prior to N4-desulfonylation (Entries 4–11, Table 6).

Table 6. Detosylation and attempted N4-and O-methylation of pentacyclic lactone 85.

a) Na·Np (8.0 equiv.), THF, –78C, 2 h, sat. aq. NH4Cl, 92%; b) See Table 6.

Entry b) Conditions Time Yield%

Attempted N4-methylation of 127

1 HCHO (50 equiv.), NaBH3CN (5.0 equiv.), AcOH (6.0 equiv.),

MeCN, rt 16 h -

2 Hünig’s (3.0 equiv.), MeI (2.0 equiv.), DMF, –78C→rt 16 h SM

3 NaH (3.0 equiv.), MeI (1.0 equiv.), THF, –78C→rt 16 h SM

Attempted O-silylation of N4-H 127

4 TBSOTf (1.5 equiv.), Et3N (2.0 equiv.), CDCl3, 0C→rt 16 h SM

5 TBSOTf (1.5 equiv.), DMAP (0.1 equiv.), Et3N (2.0 equiv.),

CH2Cl2, 0C→rt 16 h SM

Attempted O-silylation of N4-Ts 85

6 TBSOTf (1.5 equiv.), Et3N (2.0 equiv.), DMAP (0.1 equiv.),

CH2Cl2, 0C→rt 74 h SM

7 TBSCl (1.5 equiv.), imidazole (1.5 equiv.), DMF, rt 16 h SM

8 KHMDS (1.1 equiv.), TBSOTf (1.5 equiv.), CH2Cl2, –78C→rt 16 h SM

9 KHMDS (1.1 equiv.), TBSOTf (1.5 equiv.), THF, –30C→rt 16 h SM

10 KHMDS (2.5 equiv.), TBSOTf (3.0 equiv.), THF, 60C 32 h trace

11 TBSOTf (1.8 equiv.), 2,6-lutidine (3.0 equiv.), CH2Cl2, rt 48 h SM

From the table, is can be seen that O-functionalisation also proved difficult. Pentacyclic lactones

127 and 85 were unreactive to standard O-silylation conditions (Entries 4–11, Table 6, above),


85

even when forcing conditions such as extended heating with KHMDS and TBSOTf were

applied, only trace amounts of O-TBS 128 (R1=Ts) could be seen in the 1H NMR of the crude

material. At this stage, with pentacyclic lactone 85 showing unusual stability towards standard

O-silylation conditions, and having already shown that C-rather than O-methylation was

favoured, we decided to search for an alternative approach to the appropriately functionalised

E-ring.

However, during these studies we had shown that both lactam–lactone 91 and pentacyclic

lactone 85 could be deprotected using mild sodium naphthalenide conditions. We speculated also

that the free amine derivative of 85 existed partially as the zwitterion 85a in solution, rendering

the secondary amine unreactive to N4-methylation (see below).

Figure 28. Zwitterionic 85a.

For the O-functionalisation, we had found that the enolate derived from deprotonation of 85 with

either lithium or sodium bases was an unreactive nucleophile in alkylation reactions, due to the

increase stability gained by interaction with the lactone carbonyl. This could be overcome by

synthesising the potassium enolate, however this was susceptible to C-methylation. At this stage,

we attempted the partial reduction of N4- and C20-methylated compound 126a, and although the

products were not isolated, 1H NMR and IR analysis of the crude material obtained strongly

suggested that once the conjugated enol system had been broken by C19 methylation, the C21

carbonyl was readily reduced using similar DIBAL conditions to those used in our

Pictet–Spengler cyclisation step.


86

2.2.4 Ketalisation of pentacyclic lactone 85

Following failed attempts to synthesise either O-methyl or O-silyl versions of pentacyclic lactone

85, investigations into ketalisation of the C19 carbonyl moiety in pentacyclic lactone were

carried out. Although all attempts at O-functionalisation using basic conditions had failed, whilst

attempting to protect pentacyclic lactone 85 as the dimethylacetal equivalent, we had found 85 to

be a suitable substrate for acid-catalysed Michael-type additions, as discussed later in our

syntheses of alstonerinal and macroline (Scheme 49, Page 98).

As with our attempted dimethylketal formation, under standard ketalisation Dean Stark

conditions using 3.0 equivalents of ethylene glycol, sub-stoichiometric quantities of PTSA and

refluxing in toluene, an acid-catalysed Michael-addition–elimination occurred, giving rise to the

corresponding enol ether instead of the desired ketal. Application of Noyori conditions88

to enol

85 gave clean conversion into the corresponding enol ether 129 (Scheme 44, below).

Scheme 44. Attempted C19 ketalisation of lactones 85 and 91.

a) 1,2-bis(trimethylsiloxy)ethane (2.0 equiv.), TMSOTf (1 drop), CH2Cl2, –78°C, 93%.

After various C19 ketalisation conditions had instead converted either the pre-Pictet–Spengler

lactam–lactone 91 or pentacyclic lactone 85 to the corresponding enol ether, we decided to

attempt the C19 protection of β-ketoester 113 prior to the lactone E-ring formation. We

rationalised that since 113 had been shown by 1H NMR to exist predominantly as the β-keto

tautomer, the lack of 1,4-conjugation may favour ketalisation rather than the Michael addition–

elimination reaction that favoured formation of enol ethers 129.


87

Figure 29. Proposed synthesis of the E-ring via Michael addition of 130.

During the initial optimisations, Noyori conditions gave almost quantitative conversion of

β-ketoester 123 to dioxolane 130. When these conditions were repeated on larger scale, a

complex mixture of 130, 132 and 133 was isolated in good yield (Scheme 45, below). Although

the desired dioxolane was the major product, significant quantities of 132, which resulted from

the loss of the indole residue via the acid-mediated SN2’ type mechanism was observed (Scheme

43, Page 80). Interestingly, a 1,4-intramolecular Michael-type cyclisation had also occurred

between the C2 position of the indole and the C15 α,β-unsaturated lactam position.

Scheme 45. Attempted Noyori ketalisation of 113.

a) 1,2-bis(trimethylsiloxy)ethane (2.0 equiv.), TMSOTf (1 drop), CH2Cl2, –78°C→rt, 16 h, 83% 130:132:133.

That cyclisation had occurred was proven by X-ray crystal structure of 133 (Figure 30, below).

Although it was not useful for the synthesis of macroline-related indole alkaloids, we were

particularly pleased to note the acid-mediated cyclisation due to the formation of the 2-

azabicyclo[3.3.1]nonane motif that is present in many pharmaceutically important

compounds,89,90

notably the pentacyclic curans of the strychnos alkaloids91,92,

and is a motif that

is still a popular target.93


88

Figure 30. 1,4-Michael-type cyclisation following attempted Noyori ketalisation of 113.


89

2.2.5 Reduction of pentacyclic lactone 85

With efforts towards O-functionalisation of pentacyclic lactone 85 thwarted, initial investigations

into the synthesis of the (±)-alstonerine E-ring 4 via partial reduction of the C21 lactone carbonyl

in 85 were revisited. As with the previous approaches, it was rationalised that were we able to

suitably adjust the oxidation of the C21 carbonyl to the required lactol, subsequent dehydration

would furnish the carbon skeleton of the natural product. However, initial investigations into the

reduction of pentacyclic lactone 85 had shown it to be completely unreactive towards standard

reagents and conditions, such as DIBAL,94

Red-Al®,97

lithium aluminium hydride,95

L-selectride®96

and superhydride.®97

We envisaged that solvent choice and increased

temperatures may attenuate the stabilising influence of the intramolecular hydrogen bond

between the enol OH and the C21 carbonyl oxygen atom of pentacyclic lactone 85 and thus

facilitate partial reduction.

Figure 31. Proposed synthesis of of alstonerine 4 from pentacyclic lactone 85.

During initial attempts, the reducing agent was added to a solution of pentacyclic lactone 85 in

THF at –78C. The reaction mixture was then allowed to warm to room temperature overnight.

Although there are numerous procedures reported for the partial reduction of

δ-lactones in total syntheses,98,99,100

whilst using standard conditions we observed no

consumption of starting material in all cases. At this point, with a view to combining this

reduction with our previously optimised Pictet–Spengler cyclisation, we decided to focus our

efforts on effecting this transformation using DIBAL under more forcing conditions. We

envisaged that switching from the ethereal solvent THF to a non-coordinating solvent such as

CH2Cl2 or toluene should increase the reactivity of DIBAL by decreasing the stability of the

DIBAL complex. However, in practice, no reduction was observed in either of these solvents at

room temperature.


90

At this point, with numerous attempts to reduce the pentacyclic lactone 85 having returned

starting material at room temperature, the viability of heating was investigated. Although we

feared a loss of selectivity, and thus over-reduction, the reduction was attempted by refluxing

pentacyclic lactone 85 with 2.0 equivalents of DIBAL in THF. After work-up and

chromatography, diol 135 was obtained in 46% yield. Despite numerous attempts at varying

reducing agent, solvent, temperature and reagent concentration, either starting material or

over-reduced diol 135 were always achieved.

Scheme 46. Over-reduction of pentacyclic lactone 85.

a) DIBAL (2.0 equiv.), THF, 70C, 1 h, 46%, E-geometric isomer.

With diol 135 persisting in the attempts at partial reduction, the idea of continuing our synthesis

from diol 135 was briefly entertained. This would be achieved by re-establishing the E-ring via

oxidation level adjustments. Selective allylic oxidation would give unsaturated aldehyde

compound 136, which may provide a route to either type A macrolines alstonerine and

anhydromacrosalhine-methine 7, or type B macroline alstonerinal (Scheme 47, below).


91

Scheme 47. Proposed use of diol 135 in alkaloid synthesis.

a) COCl2 (1.4 equiv.), DMSO (2.8 equiv.), Et3N (excess), –78C→rt, 2 h. 97%.

135 was added to a solution of DMSO, Et3N and COCl2, which led to oxidation of the allylic

alcohol moiety. In addition to allylic oxidation, elimination of the C17 alcohol occurred. This

gave exocyclic methylene compound 137 as the major product in 97% yield. Although, it was

feasible that 137 could have been converted into alstonerine,3 the route would have involved

numerous oxidation level adjustments, and, as such, this approach was abandoned.


92

2.2.6 Alternative routes to the alstonerine E-ring

After numerous unsuccessful attempts at O-functionalisation of pentacyclic lactone 85, and

having failed to find suitable conditions to adjust the oxidation of its E-ring to that required for

alstonerine, an alternative approach to the synthesis was briefly investigated. The aim was to

install the correct E-ring via either base-mediated Michael-type addition to 3-butyn-2-one 21 or

acid-catalysed addition to trans-4-methoxy-3-buten-2-one 142 (Figure 32, below).

Figure 32. Proposed synthesis of the E-ring via Michael-type addition to either 21 or 142.

The former approach, although very similar to that applied in Cook’s first synthesis

(Scheme 5, Page 20) was quickly abandoned, as polymerisation side-reactions were difficult to

avoid, both during the synthesis of 3-butyn-2-one 21 and during the Michael-addition with 90.

During early investigations into the latter approach, Lactam–alcohol 90 was converted into

β-keto acetal 141a by reaction of 90 with trans-4-methoxy-3-buten-2-one 142 and

sub-stoichiometric quantities of triflic acid at –78°C (Table 7, below). This gave epimeric

β-keto acetals 141a in 97% yield, and provided evidence to suggest that the desired enol

intermediate 141 (Figure 32, above) had been formed during the course of the reaction, although


93

the second Michael-type addition cyclisation had not occurred under these conditions. It was

envisaged that a second intramolecular Michael-type addition may be induced either basic

conditions, or by heating in the presence of acid. We also hoped that heating the initial acid-

catalysed intermolecular Michael-type reaction of 90 with trans-4-methoxy-3-buten-2-one 142

may bring about an irreversible cyclisation and complete the tandem double Michael-addition E-

ring synthesis.

For the optimisation, we found that treating intermediate acetal 141 with sodium methoxide gave

no reaction at either –78°C or room temperature (Table 7, below). The trans-4-methoxy-3-buten-

2-one 142 substrate had been synthesised by heating acetylacetaldehyde dimethyl acetal with

sodium methoxide in methanol. Interestingly, when 141 was heated in methanol with excess

sodium methoxide under microwave conditions, 1H analysis of the crude material suggested that

N4-deprotected lactam 143 was the major product, however this was not isolated by

chromatography. At this stage, we hoped that heating 143 under acidic conditions would

facilitate the required 1,4-addition. However, C2–C15-cyclisations had also been shown to be

possible under these conditions (Scheme 45, Page 87).

Table 7. Michael addition of 90 to trans-4-methoxy-3-buten-2-one 142.

a) trans-4-methoxy-3-buten-2-one (10.0 equiv.), TfOH (1 drop), CH2Cl2, –78°C→rt, 2 h, 97%; b) see Table 7.

Entry a) Conditions Product

1 KHMDS (0.5 equiv.), THF, –78°C→rt, 24 h -

2 NaOMe (1.0 equiv.), MeOH, 140°C µW, 0.5 h 143

3 NaOMe (0.1 equiv.), MeOH, –78°C→rt, 24 h -

4 TMSOTf (0.1 equiv.), CH2Cl2, –78°C→rt, 16 h -


94

Although at this stage we had failed to complete the double Michael-type addition, we had

isolated N4-H vinylogous ester 143 in moderate yield, from which we envisaged the synthesis of

the E-ring could be completed by a Baylis–Hillman-type cyclisation.

Figure 33. Baylis–Hillman approach to alstonerine E-ring in 144.

Although we were optimistic that treatment with nucleophilic amine base would bring about the

E-ring cyclisation, before we could begin our optimisations, we found that the alstonerine carbon

skeleton could be synthesised from lactam–lactone 91 in two steps, and therefore our

Baylis–Hillman approach was abandoned in favour of the final approach to alstonerine.


95

2.2.7 Total synthesis of type A macroline-related indole alkaloid alstonerinal 138

During our continued attempts to synthesise the E-ring of type B macroline indole alkaloid

alstonerine 4, we became interested in the corresponding type A macroline

alstonerinal 138. Compound 138 can also be found in the stem-bark extract of both Alstonias

angustifolia101

and macrophylla102

and is an isomer of both our target compound alstonerine 4,

and the lactone containing alkaloid alstolactone 145, whose synthesis is discussed later.

Alstonerinal 138 differs only from alstonerine in the E-ring, which contains a C17–O–C19

linkage rather than the C17–O–C21 linkage of alstonerine 4. Whereas it is hard to imagine the

transformation of alstolactone 145 to alstonerine 4 occurring in a single step, we thought it

feasible that under certain conditions, the interconversion of type A and B macrolines may be

achieved.

Figure 34. Structural relationship of type B macroline alstonerine 4 its type A isomer 138.

We first observed the type A macroline structure whilst attempting to tautomerise pentacyclic

enol 85, and protect the C19 carbonyl of the consequent β-ketoester as the corresponding

dimethyl ketal 145 (Figure 35, below). Upon successful protection, treatment of 143 with

DIBAL would effect the desired partial 1,2-reduction of the C21 lactone carbonyl, rendering the

tosyl protected natural product 134. Desulfonylation and methylation would complete the

synthesis of (±)-alstonerine 4 (Figure 35, below).

For the synthesis of dimethyl ketal 145 we predicted that treating pentacyclic lactone 85 with

sub-stoichiometric quantities of Brønsted acid in excess methanol would lead to the

β-keto tautomer, the addition of dehydrating agent trimethyl orthoformate would then drive the

equilibrium towards the formation of dimethyl ketal 145.


96

Figure 35. Proposed synthesis of (±)-alstonerine.

Initial attempts at ketalisation using 3Å molecular sieves as the dehydrating agent showed no

conversion at room temperature. Switching from sieves to trimethyl orthoformate as the

dehydrating agent led to the formation of two isomeric compounds (isomer ratio 2:1) in 91%

yield. Based on interpretation of the 1H and

13C spectra, these were initially considered to be

geometric isomers of type B macroline methyl ester 147. However, analysis of the IR spectra and

comparison to known compounds101,102

suggested that the major isomer was the result of a

rearrangement in the E-ring,103

corresponding to type A macroline methyl ester 148. The minor

isomer was assigned as type B macroline E-methyl ester 147 (Scheme 48, below). These

assignments were confirmed by HMBC NMR.

Scheme 48. Acid-catalysed rearrangement of pentacyclic lactone 85 to type A analogue 148.

a) CSA (0.1 equiv.), HC(OMe)3 (1.5 equiv.), MeOH/CH2Cl2, rt, 16 h, 91% (2:1 ratio of 148:147); b) CSA (0.1

equiv.), HC(OMe)3 (2.0 equiv.), MeOH/CH2Cl2, reflux, 72 h, 67% 148.


97

We expected that decreasing the reaction temperature would influence this ratio in favour of the

desired type B compound 147. Unfortunately the (2:1 148/147) ratio persisted when the reaction

was carried out at room temperature over extended time periods of over three days. In turn

extended reflux at 70C for 72 hours favoured the rearrangement product 148 in 67% yield (3:1

148/147). We envisaged the ratio may yet be inverted by decreasing the temperature to –78C

and using catalytic super acidic reagent, such as triflic acid, to increase the reactivity, however at

this point we chose to investigate the potential reductions of 148 and 147 to give the carbon

skeletons of alstonerinal and alstonerine respectively.

For the conversion of 148 into alstonerinal, sodium naphthalenide was again chosen as our first

attempt at the N4-detosylation (Scheme 49, below). Treatment of type A macroline methyl ester

148 with a ~2M solution of sodium naphthalenide in THF at –78C gave the free N4-H amine

149 in 92% yield. Previous attempts at N4-methylation using reductive amination with

formaldehyde had failed, thus similar conditions to those outlined in Martin’s alstonerine

synthesis were chosen (Scheme 18, Page 32).3 The addition of excess Hünig’s base and

iodomethane at –78C in THF and warming to room temperature overnight gave alstonerinal

precursor 150 in 87% yield. At this stage we faced the often problematic task of the partially

reducing the C21 methyl ester functionality of 150. Initial attempts carried out using both Red-Al

and DIBAL failed to give the natural product 138, but gave the over reduced allylic alcohol 151

in good yield, and L-selectride showed no reaction. Literature precedent for the reduction of

vinylogous carbonates such as 150 often favours a two-step process, presumably due to the

relative ease of the complete reduction and allylic oxidation.104,105

We were also encouraged as

alcohol 151 was a known compound, and was reported as the result of NaBH4 reduction of

alstonerinal 138. Allylic alcohol 151 had also been oxidised to alstonerinal using MnO2 by Kam

et. al. in the isolation paper.102

However, initial attempts at the oxidation using MnO2 proved

difficult, therefore Dess-Martin oxidation conditions106

were used, giving rise to alstonerinal,

albeit in minute quantities (Scheme 49, below).


98

Scheme 49. Completion of the (±)-alstonerinal synthesis.

a) Na·Np (8.0 equiv.), THF, –78C, 2h 30 min, 92%; b) Iodomethane (1.4 equiv.), Hünig’s (3.0 equiv.), THF, –78C

→ rt, 16 h, 81%; c) DIBAL (1.0 equiv.), toluene, –92C, 1 h, 99%; d) Dess-Martin Periodinane (1.5 equiv.),

pyridine (3.0 equiv.), CH2Cl2, 0C, 2 h, 13% + SM recovery.


99

2.2.8 Synthesis of N4-tosyl-macroline 152

With type B macroline E-methyl ester 147 in hand, albeit in disappointing yield, we attempted

the final steps of our original approach to alstonerine 4.

Figure 36. Proposed alstonerine synthesis from type B methyl ester 147.

We again hoped that partial 1,2-reduction of the C21 lactone carbonyl followed by

acid-catalysed hydrolysis would give tosyl protected alstonerine 134. We rationalised that the

N4-desulfonylation and methylation required to complete the synthesis would be achievable

either pre- or post-reduction. For the reduction we again turned to previously successful

conditions. After treatment with DIBAL in CH2Cl2 at −78C for 1 hour, TLC assay showed the

formation of a new product. Following work-up with Rochelle salt and chromatography, NMR

analysis showed the appearance of two new low field singlets at ~ δ 6.00 and 5.60 corresponding

to the methylene protons of N4-Ts-macroline 152. Comparison of the IR with that of the known

compound confirmed the presence of the ring-opened unsaturated ketone in the

E-ring.3

Scheme 50. DIBAL reduction of methyl ester 147 to give N(4)-Ts-macroline 152.

a) CSA (0.1 equiv.), HC(OMe)3 (1.5 equiv.), MeOH/CH2Cl2, rt, 16 h, 91% (2:1 ratio of 148:147); b) DIBAL (1.1

equiv.), CH2Cl2, –78C, 1 h, 32% + SM recovery.


100

The N4-methyl macroline precursor 153 was prepared using sodium naphthalenide

desulfonylation conditions, followed by treatment with iodomethane and Hünig’s base. This

gave macroline precursor 153 in excellent yield over two steps.

Scheme 51. Synthesis of macroline precursor 153.

a) Na·Np (5.0 equiv.), THF, –78C, 2 h, 86%; b) Iodomethane (1.4 equiv.), Hünig’s (3.0 equiv.), THF, –78C → rt,

16 h, 81%.

With macroline precursor 153 in hand, repeating the reduction conditions that had been carried

out on the N4-tosyl equivalent would provide macroline 1. However, at this late stage of the

project, all efforts were focused on the synthesis of alstonerine.


101

2.2.9 Towards the synthesis of (±)-alstolactone

Alstolactone 145 is a macroline-related indole obtained from the leaf extract of Alstonia

angustifolia var. Latifolia.,101

and is the only example from the macroline indole family to

contain a lactone functionality in the E-ring. As such it’s synthesis was investigated as a possible

precursor to alstonerine 4.

With pentacyclic lactone 85 in hand, activation of the C-19 carbonyl as the corresponding enol

triflate 154 and subsequent hydrogenolysis would give N4-tosyl-alstolactone 155, and

desulfonylation would deliver the desired N4-H natural product 145 (Figure 36).

Figure 36. Proposed synthesis of alstolactone 155 and possible entry to sarpagine-related 28.

Although early work focused on their use as precursors to vinyl cations and alkylidene carbenes,

vinyl triflates have since been found to be excellent cross-coupling partners. This has led to

extensive reviews on their synthesis from carbonyl groups and subsequent applications.107

The

synthesis of enol triflate 154 was initially carried out by treating pentacyclic lactone 85 directly

with trifluoromethanesulfonic anhydride in the presence of non-nucleophilic base.108

When Et3N

was used as the base in CH2Cl2 at room temperature a mixture of geometric isomers was

obtained (3:2 154/155) in 32% yield (Entry 1, Table 8). Switching base from Et3N to Hünig’s


102

base had little effect on the (Z-:E-) ratio. An improved ratio of (2:1 154/155) in 63% yield was

obtained by decreasing the equivalents of triflic acid, reaction concentration and temperature

(Entry 3, Table 8).

Table 8. Synthesis of β-ketoester enol triflates 154/155.

Entry a) Conditions Ratio 154:155

Yield 154

1 Et3N (3.0 equiv.), Tf2O (1.5 equiv.), CH2Cl2, rt, 1 h. ~3:2 32

2 Hünig’s (3.0 equiv.), Tf2O (1.5 equiv.), −50C, 30

min.

~3:2 55

3 Et3N (2.0 equiv.), Tf2O (1.5 equiv.), −78C, 30 min. ~2:1 63

A more detailed optimisation of this reaction can be found on pages 108 to 110.

There are two approaches that dominate literature procedures for the palladium-catalysed

reduction of vinyl triflates. The transformation can be achieved using either tributyltin

hydride,109

or triethylsilane109

as the hydrogen donor, with catalytic Pd0 in the presence of lithium

chloride. Conditions using Et3N and formic acid together with catalytic Pd(OAc)2 and Ph3P are

also prevalent.110

We chose the latter for the hydrogenolysis of enol triflate 154 into the N4-tosyl

protected natural product 155.

Microwave modified conditions similar to those of Trudell were used.111

Enol triflate 154 was

heated in the microwave for 20 minutes at 80C with sub-stoichiometric Pd(OAc)2, and Ph3P in

excess Et3N, formic acid and DMF. Filtration over celite, followed by washing with aqueous

5% LiCl solution and chromatography gave N4-tosyl-alstolactone 155 in 44% yield. This was

improved to 73% when chromatography was carried out immediately upon reaction completion

(Scheme.


103

Scheme 52. Hydrogenolysis of enol triflate 155 and desulfonylation to alstolactone 145.

a) Pd(OAc)2 (0.1 equiv.), Ph3P (0.3 equiv.), HCO2H (2.0 equiv.), Et3N (3.0 equiv.), DMF, 80C, 20 min, 73%;

b) Desulfonylation conditions.

At this stage, all that remained to complete the synthesis was to remove the N4-tosyl protecting

group. Strongly acidic conditions reported for this transformation, such as HBr and phenol in

refluxing acetic acid,112

or HClO4113

were avoided in order to alleviate rearrangement of the

E-ring. The previously successful sodium naphthalenide conditions gave no conversion into the

natural product, and led to degradation of 155. The competitive reduction of the α,β-unsaturated

lactone E-ring was suspected as causing the poor reactivity. Several other recently documented

methods of sulfonamide cleavage also failed to complete the synthesis alstolactone. These were:

SmI2/amine and water in THF,114

magnesium in anhydrous methanol under ultrasonic

conditions115

and TBAF in THF, under both prolonged reflux and microwave heating.116

In all

cases starting material was recovered in quantitative yield.

2.2.10 Synthesis of N4-tosyl-(±)-anhydromacrosalhine-methine 7

As multiple attempts at the deprotection of N4-tosyl-alstolactone had failed, focus was returned to

synthesising of the alstonerine E-ring. With 155 in hand, we hoped to probe the reactivity of the

cyclic conjugated oxonium ion intermediate 156 that would result from a 1,2-reduction of its

lactone carbonyl and subsequent acid-catalysed dehydration. We expected that under aqueous

conditions, intermediate 156 may react with hydroxide to give epimeric allylic alcohol 158 and

that a Swern oxidation (Cook3 Scheme 6, Page 21) and desulfonylation/methylation would give

alstonerine. Alternatively, anhydrous acidic conditions may effect a 1,4-elimination to give

conjugated diene 157. At which point, desulfonylation/methylation would give

(±)-anhydromacrosalhine-methine 7 and Wacker-Tsuji oxidation of 157 may provide access to

alstonerine E-ring.


104

Figure 37. Proposed use of N4-tosyl alstolactone 155 as an intermediate for alkaloid synthesis.

The synthesis of anhydromacrosalhine-methine 7 would also offer a potential synthetic route to

antiamoebic bis(indole) alkaloids, and is a known intermediate17

in Cook’s total synthesis of

macrocarpamine117

8 (the most potent of the Alstonia angustifolia bis(indole)s used against

amoebic dysentery by the people of Malaya118

).

Figure 38. Cook’s partial synthesis of macrocarpamine 8 from 7.


105

In practice, when N4-tosyl alstolactone 155 was treated with DIBAL in CH2Cl2 at −78C for 3

hours, TLC assay of the crude material showed that multiple new products had been formed.

Four products were separated using preparative TLC, however 1H NMR analysis illustrated that

all four products had undergone further reaction during purification, to give a single new

product. The 1H NMR analysis showed that the unusually low field quartet of doublets at δ 7.11

and the methyl doublet at δ 1.45 of 155 had been replaced with a new doublet of doublets at

δ 6.00 and doublets at δ 4.57 and δ 4.38. These corresponded to the olefinic protons of N4-tosyl-

(±)-anhydromacrosalhine-methine 157.

Scheme 53. DIBAL reduction of N4-tosyl-alstolactone 155.

a) DIBAL (1.1 equiv.), CH2Cl2, −78C, 3 h, 94%; b) Silica, CH2Cl2, 15 min, 100%.

Having found reducing N4-tosyl alstolactone 155 with DIBAL gave only the conjugated diene

157 and no epimeric allylic alcohols 158 that we had hoped to isolate, the Swern approach to

alstonerine was abandoned. For the oxidation of diene 157, Wacker–Tsuji oxidation

conditions119

were attempted. However, extended reflux led only to loss of the terminal alkene,

with no formation of the C19 ketone of alstonerine.

Scheme 54. Attempted Wacker–Tsuji oxidation of 157.

a) PdCl2 (0.1 equiv.), CuCl2 (2.1 equiv.), DMF: H2O (5:1), 95°C, 16 h.


106

2.2.11 Total synthesis of (±)-alstonerine

At this stage the utility of the hydroxymethyl-substituted aziridine based approach to macroline-

related indole alkaloids had been proven by the total synthesis of alstonerinal 138. Pentacyclic

lactone 85 had also been be converted into the N4-tosyl protected derivatives of alstolactone 155,

anhydromacrosalhine-methine 157 and macroline 152 (the compound after which the family of

alkaloids is named), however it remained to complete our alstonerine 4 synthesis.

Figure 39. The Craig group’s approach to macroline-related indole alkaloids.

Pentacyclic 85 was found to be readily available by partial reduction of the C3 carbonyl in

lactam–lactone 91 using DIBAL, followed by triflic acid mediated Pictet–Spengler cyclisation.


107

The C19 carbonyl of 85 had been reduced using palladium-catalysed hydrogenolysis of the enol

triflate 154, and the C21 lactone carbonyl had also been reduced by first converting 85 into the

corresponding methyl enol ether. This negated the stabilising effect of the intramolecular

hydrogen bond, and lead to the synthesis of the ring-opened macroline E-ring.

Therefore, despite numerous attempts, the partial reduction of the C21 lactone carbonyl group

and subsequent C20‒C21 double bond-forming acid-catalysed dehydration was yet to be

accomplished.

For the final approach to the E-ring, we reasoned that functionalisation of the C19 enol with an

electron-withdrawing group may render the C21 lactone carbonyl more electron-deficient, and

therefore more reactive towards partial reduction. In addition, optimisation studies of the

Pictet–Spengler cyclisation (Scheme 43, Page 80) had shown that stoichiometric quantities of

triflic acid were required to convert partially reduced lactam–lactone 91 into pentacyclic lactone

85. With this in-mind, it was hoped that on partial reduction of enol triflate 161 (Figure 40,

below) and hydrolysis of partially reduced triflate intermediate 162, an equivalent of triflic acid

would be released, which would in turn mediate the Pictet–Spengler cyclisation, as shown below.

Figure 40. Proposed synthesis of alstonerine 4.


108

Pentacyclic triflate 154 was chosen to initially probe what would constitute the final stages of the

envisaged reduction–Pictet–Spengler reaction. 154 was converted into lactol intermediate 163

using DIBAL. At this stage we were delighted to observe that only a proton NMR of an

intermediate, assumed to be 163, could be obtained before a colour change from colourless to

dark brown was observed in the NMR sample. 1H NMR analysis of the sample following the

colour change showed that spontaneous triflate hydrolysis had occurred, facilitating the C20‒

C21 double bond-forming acid-catalysed dehydration. N4-Tosylalstonerine was isolated in

quantitative yield following chromatography.

Scheme 55. DIBAL reduction of enol triflate 154.

a) DIBAL (1.5 equiv.), CH2Cl2, −78C, 3 h; b) CDCl3, 1 h, 100%.

Encouraged by finally having established the alstonerine E-ring, we attempted to combine this

reduction with the Pictet–Spengler cyclisation, in a one-pot reduction–Pictet–Spengler

cyclisation of enol triflate 161 that would provide the polycyclic core of alstonerine. During the

reaction the enol triflate would serve the multiple purposes of protecting the C19 ketone from

reduction whilst simultaneously activating the C21 carbonyl, and as a latent reagent for the

Pictet–Spengler cyclisation and acid-catalysed dehydration.

For the synthesis of enol triflate 161, our first attempt returned to those conditions used in our

synthesis of N4-tosyl-alstolactone 155. Lactam–lactone 91 was treated with triflic anhydride in

the presence of non-nucleophilic amines Hünig’s base and triethylamine in CH2Cl2 at low

temperatures (Entries 1 and 2, Table 10, below). The 1H NMR spectra of the crude material

obtained from both reactions showed that two products had been formed, yet both gave low

yields of 161 following chromatography. In an attempt to improve on this yield, the reaction was

run in various solvents. Triflic anhydride reacted with THF to give bis-triflylbutane, with

complete starting material return (Entry 15, Table 10). The combination of CH2Cl2 as a solvent


109

and organic bases gave poor Z- selectivity (Entries 1–4, Table 10). Interestingly the E-isomer

was never isolated. Instead its existence in the crude material was assumed via a process of

elimination. During early attempts at enol triflate formation (Entries 1–4, Table 10), complete

conversion of starting material was observed by TLC assay, and confirmed by 1H NMR analysis

of the crude material obtained which showed that a mixture of two products had been formed.

However following chromatography, only mixtures of the desired Z-isomer 161 and starting enol

91 were isolated. It was assumed that mixtures of geometric isomers were formed during the

reaction, but the E-isomer was unstable towards hydrolysis on silica. This assumption was

further supported by attempts to isolate both the sodium and potassium enolates of 91. When

enol 91 was subjected to exact repeats of the triflylation conditions (Entries 8 and 9, Table 10)

without triflylating agent, 1H NMR analysis of the crude material obtained from identical work-

ups to those used in the synthesis of 161, showed only clean starting material 91. The next

attempt was to switch to KHMDS, in order to form a potassium enolate that was previously

shown to be reactive to C-alkylation (Table 5, Page 83). This led to increased reactivity, and

favoured the desired Z-isomer, yet the yield was still poor. We hoped that switching to co-

ordinating ethereal THF may increase the reactivity of the enolate intermediate; therefore we

required an alternative triflylating agent to triflic anhydride, as this had been shown to react with

THF. Lactam–lactone 91 was converted cleanly into Z-enol triflate 161 using 1.1 equivalents of

KHMDS and N-phenyl-bis(trifluoromethanesulfonamide).120

Importantly, no E-isomer was

observed in the 1H NMR of the crude material. Notably, when DMF was used as the solvent,

allene 165 was achieved as the major product after 15 minutes at –78°C (Entry 13, Table 10).

When treated with DIBAL, allene 165 was converted into inseparable mixtures of N4-tosyl-

alsoterinal and the N4-tosyl derivative of alstonerinal precursor allylic alcohol 151 in good yield.

When aqueous conditions were applied to lactam–lactone 91 (Entry 17, Table 10),121

only

starting material was obtained, possibly due to the formation of only the E-isomer.


110

Table 10. Synthesis of enol triflate 161.

Entry a) Conditions Temp ~ Ratioa

161:164:

165

Yieldb

165

1 Hünig’s (3.0 eq.), Tf2O (1.2 eq.), CH2Cl2, 0.5 h −78°C 1:5:1 6%

2 Et3N (1.5 eq.), Tf2O (1.2 eq.), CH2Cl2, 0.5 h −78°C 1:2:0 22%

3 Hünig’s (3.0 eq.), Tf2NPh (1.2 eq.), CH2Cl2, 0.25 h rt 1:5:0 11%

4 Hünig’s (3.0 eq.), Tf2NPh (1.2 eq.), CH2Cl2, 0.5 h −78°C 0:1:0 SM

5 Hünig’s (3.0 eq.), Tf2NPh (1.2 eq.), CH2Cl2, 3.0 h −78°C 0:1:0 SM

6 KHMDS (1.5 eq.), Tf2NPh (1.1 eq.), CH2Cl2, 3.0 h −78°C→rt 1:1:0 14%

7 DBU (1.5 eq.), Tf2NPh (1.1 eq.), CH2Cl2, 3.0 h −78°C→rt 1:9:0 -

8 KHMDS (1.5 eq.), Tf2NPh (1.1 eq.), CH2Cl2, 16 h −78°C→rt 1:3:0 23%

9

10

NaH (1.0 eq.), Tf2O (1.1 eq.), CH2Cl2, 16 h

KHMDS (1.2 eq.), Tf2NPh (1.1 eq.), THF, o/n

0°C→rt

−78°C→rt

1:5:0

5:1:0

SM

74%

11 NaH (1.0 eq.), Tf2O (1.1 eq.), THF, 16 h 0°C - -

12 KHMDS (1.1 eq.), Tf2NPh (1.1 eq.), THF, 16 h −78°C→rt 5:1:0 69%

13 Hünig’s (3.0 eq.), Tf2NPh (1.1 eq.), DMF, 0.5 h −78°C 1:0:11 88%

14 DBU (3.0 eq.), Tf2NPh (1.2 eq.), THF, 16 h rt 1:9:0 SM

15 DBU (3.0 eq.), Tf2O (1.2 eq.), THF, 0.25 h −78°C 0:0:0 SM

16 NaH (5.0 eq.), Commins (2.0 eq.), THF, 1 h 0°C - -

17 LiOH (5.0 eq.), Tf2O (2.5 eq.), toluene, H20 1 h 0°C 0:1:0 SM

18 KHMDS (1.1 eq.), Tf2NPh (1.1 eq.), toluene, 16 h −78°C→rt 1:5:0 SM

aRatio of 161:164:165 visible in

1H NMR of crude material, during chromatography 164 underwent hydrolysis to

give only SM 91; bIsolated yield following chromatography


111

Having established a reliable method for converting lactam–lactone 91 into Z-enol triflate 161,

the stage was set for our postulated one-pot reduction–dehydration–Pictet–Spengler cyclisation.

Previously, we had shown that the enol-triflate E-ring of 154 was converted into the

appropriately functionalised E-ring for alstonerine in tosyl protected 134 (Scheme 55, Page 108).

We had also shown that an equivalent of triflic acid was required to complete the Pictet–

Spengler cyclisation of 91 to pentacyclic lactone 85 (c, Scheme 43, Page 80). We were delighted

to observe that treatment Z-enol triflate 161 with 2.25 equivalents DIBAL, followed by wet

Et2O–Rochelle salt work-up gave an unstable intermediate, presumed to be the crude

hemiaminal–lactol 162. Upon stirring in wet CH2Cl2 or K2CO3 treated CDCl3, 162 underwent

triflic acid elimination and instantaneous Pictet–Spengler cyclisation, to give cleanly

N4-tosylalstonerine 134 in excellent yield and as the sole product, as observed by 1H NMR.

Overjoyed with the success of our one-pot reduction–dehydration–Pictet–Spengler cyclisation,122

all that remained to complete the synthesis was desulfonylation and alkylation. Having achieved

this transformation during our total synthesis of alstonerinal, we first turned to sodium

naphthalenide conditions. Treatment of N4-tosylalstonerine with 8.0 equivalents sodium

naphthalenide solution in THF at –78C gave N4-demethylalstonerine in 57% yield. A loss of the

dark green colour during this reaction indicated that over reduction of the enone moiety in the E-

ring may be occurring due to the excess reducing agent. When the concentration of sodium

naphthalenide was reduced to 5.0 equivalents, 134 was converted into N4-demethylalstonerine

166 in 83% yield. Various alternative desulfonylation conditions were attempted, however all

failed to improve on this yield. The synthesis was completed using the methylation conditions

outlined previously (Scheme 49, Page 98). Iodomethane was added to N4-demethylalstonerine

166 and excess Hünig’s base in THF at –78C, giving alstonerine 4 in 91% yield (Scheme 56,

below). This led to the synthesis of alstonerine in just 8 steps from hydroxymethyl substituted

aziridine 82 and in an overall yield of 37%. Aziridine 82 and sulfone 88 were previously shown

to be readily accessible (Schemes 25 and 28 respectively).


112

Scheme 56. Final FGI and completed total synthesis of alstonerine 4.

a) Sulfone 88 (1.5 equiv.), n-BuLi (2.8 equiv.), THF, –78°C→rt o/n, then aqueous 2M HCl, 80%; b) TMA (1.5

equiv.), toluene, 120°C, 2 h, saturated aqueous Rochelle salt, 94%; c) 4H-2,2,6-trimethyl-1,3-dioxin-4-one (1.5

equiv.), toluene, 150°C µW, 20 min, 97%; d) DBU (2.0 equiv.), THF, rt, 12 h, 93%; e) KHMDS (1.2 equiv.),

Tf2NPh (1.1 equiv.), THF, –78°C→rt, o/n, 74%; g) DIBAL (2.5 equiv.), CH2Cl2, −78C, 2.25 h, then wet CH2Cl2, 1

h, 98%; g) Na·Np (5.0 equiv.), THF, –78C, 2 h, 83%; h) Iodomethane (2.0 equiv.), Hünig’s (3.0 equiv.), THF, –

78C→rt, 16 h, 91%.


113

2.2.12 Improved route to N4-tosylanhydromacrosalhine-methine 157

As with our total synthesis of alstonerine, we envisaged the synthesis of

(±)-anhydromacrosalhine-methine 7 via a reduction–Pictet–Spengler cyclisation of intermediate

167. The E-ring of intermediate 167 would be synthesized by hydrogenolysis of enol triflate 161.

Scheme 57. Proposed synthesis of N4-Tosylanhydromacrosalhine-methine 157.

Enol triflate 161 was converted into Pictet–Spengler cyclisation precursor 167 in an improved

yield of 85%. We now envisaged that DIBAL reduction followed by acid-catalysed dehydration

would give us N4-tosylanhydromacrosalhine-methine 157. However, in practice, when 167 was

reacted with DIBAL and subjected to acidic work-up with triflic acid, a complex mixture of

pentacyclic products was isolated. The conjugated diene E-ring of 157 is known to be

acid-sensitive, thus in order to complete our improved synthesis of anhydromacrosalhine-

methine, optimisation of the acidic Pictet–Spengler and 1,4-elimination conditions is required.

Scheme 58. Failed tandem reduction–Pictet–Spengler cyclisation of 167.

a) KHMDS (1.2 equiv.), Tf2NPh (1.1 equiv.), THF, –78°C→rt o/n, 74%; b) Pd(OAc)2 (0.1 equiv.), Ph3P (0.3

equiv.), HCO2H (4.0 equiv.), Et3N (3.0 equiv.), DMF, 80C, 20 min, 85%; c) DIBAL (2.0 equiv.), CH2Cl2, −78C, 3

h, then TfOH (2.5 equiv.), rt, 15 min, degradation.


114

2.2.13 Extension of methodology

Having successfully applied our aziridine ring-opening based synthesis of

α,β-unsaturated-δ-lactam 90 to the total synthesis of alstonerine 4, our attention turned to

extending the scope of this sequence, by synthesising optically pure lactams 168a. We hoped to

show that, α,β-unsaturated-δ-lactams 168, in addition to themselves being useful building blocks

in organic synthesis, can be partially reduced which allows them to participate in

tetrahydropyridine-like chemistry, as outlined previously (Figure 8, Page 34).

We also hoped that the ring opening of optically pure hydroxymethyl-substituted aziridines 169

would allow access to bis-substituted lactams 168b. In addition, by altering the configuration of

aziridines 169, an enantiospecific route to each of the four possible enantiomers of lactam 168

would be possible.

Figure 41. Synthesis of optically pure amino acid-derived lactams 168.

We began by investigating the synthesis of optically pure D-leucine-derived α,β-unsaturated

δ-lactam 171. L-leucine was first converted into aziridine 172 in 56% yield using a sequence

previously reported by the Craig group.123

Aziridine 172 was then reacted with the lithiated

anion of nucleophile trimethyl 3-(phenylsulfonyl)orthopropionate 88. Acidic work-up gave

epimeric sulfones 173 in excellent yield. Compound 173 was then treated with

trimethylaluminium under the microwave conditions, as outlined in our alstonerine total

synthesis. This gave a mixture of the desired α,β-unsaturated lactam 171, the intermediate

piperidine 174 and trans-α,β-unsaturated non-cyclised methyl ester 175, which as previously,

could not be converted into the desired heterocycle 171.


115

Scheme 59. Synthesis of optically pure α,β-unsaturated lactam 171.

a) trimethyl 3-(phenylsulfonyl)orthopropionate 88 2.0 (equiv.), n-BuLi (4.0 equiv.), THF, –78°C→rt, 16 h, 82%

(7:3 sulfone epimers); b) TMA (1.1 equiv.), toluene, 150°C, 30 min, saturated aqueous Rochelle salt, 93%

conversion as a mixture of 171, 174 and 175.

Importantly, intermediate 174 was converted into the desired compound 171 by resubmission to

the original reaction conditions. At this stage, having shown that optically pure mono-substituted

lactam 171 was available from the L-leucine, the synthesis of bis-substituted lactams 168b was

briefly investigated. Racemic anti-substituted aziridine 176 was chosen as our first substrate, as

we hoped to provide evidence to support our assumption that anti-substituted aziridine 176

would provide syn-substituted α,β-unsaturated lactam 177.

In practice, anti-substituted 176 was converted into the corresponding lactones 178 as a 2:1

mixture of sulfone epimers. Lactones 178 were then converted into α,β-unsaturated lactam 177 in

good yield using the previously established trimethylaluminium microwave conditions.

Importantly the corresponding α,β-unsaturated ester 179 was avoided by isolating lactones 178 in

place of the open-chain methyl ester. We hope that exposing 177 to acidic conditions will bring

about a similar cyclisation similar to that seen with our indole containing substrate (Scheme 45,

Page 87). This will provide a selective route to the benzomorphan containing alkaloids, which

include numerous important pharmaceutical compounds.124


116

Scheme 60. Synthesis of syn-substituted racemic α,β-unsaturated lactam 177.

a) trimethyl 3-(phenylsulfonyl)orthopropionate 88 2.0 (equiv.), n-BuLi (4.0 equiv.), THF, –78°C→rt, 16 h, 87%

(2:1 sulfone epimers); b) TMA (1.5 equiv.), toluene, 150°C, 10 min, saturated aqueous Rochelle salt, 56% and SM

recovery.

We also aimed to investigate selectivity the nucleophilic ring-opening reaction of aziridine 180

which contains both our directing hydroxymethyl-substituent and a phenyl-substituent that also

has a directing effect (Scheme 61, below).

Figure 42. Selectivity of aziridine 180 with both phenyl- and hydroxymethyl-directing groups.

Aziridine 180 was synthesised from cinnamyl alcohol using Sharpless conditions69

and subjected

to our standard aziridine ring-opening condition. Unfortunately, this gave a very complicated

mixture of products, from which only those products of phenyl-directed aziridine ring-opening

183 were isolated in suitable yield for complete characterisation (Scheme 61, below).


117

Scheme 61. Ring-opening of aziridine 180.

a) trimethyl 3-(phenylsulfonyl)orthopropionate 2.0 (equiv.), n-BuLi (4.0 equiv.), THF, –78°C→rt, 16 h, 67%

of complex mixture of Phenyl-directed aziridine ring-opening.


118

2.2.14 Conclusion

We report the concise aziridine-based total syntheses of macroline-related indole alkaloids

(±)-alstonerine122

4 and (±)-alstonerinal 138, which were achieved in eight and ten steps

respectively from hydroxymethyl-substituted aziridine 81. We also showed our approach to be

amenable to the synthesis of related compounds macroline 1, alstolactone 145 and

anhydromacrosalhine-methine 7 by synthesising their N4-tosyl derivatives 152, 155 and 157, the

latter of which provides access to the bis-indole alkaloids, particularly macrocarpamine 8.

Figure 43. Alkaloids synthesised from lactam–lactone intermediate 91.

Late-stage intermediate lactam–lactone 91 was rapidly assembled from three simple components

in four high-yielding steps, those being hydroxymethyl-substituted aziridine 82, and trimethyl 3-

(phenylsulfonyl)orthopropionate 88 and 4H-2,2,6-trimethyl-1,3-dioxin-4-one 115.


119

Figure 44. Late stage intermediate 91 synthesised from three simple components.

We have also shown this approach to macroline-related alkaloids to be amenable to the synthesis

of the indolomorphan motif, by an intramolecular acid-mediated Michael-type addition that was

used to synthesise 133 (Figure 45, below).

Figure 45. Synthesis of the indolomorphan motif, by an intramolecular acid-mediated

Michael-type addition.

In addition, α,β-unsaturated lactam 177 was also synthesized, from which we hope that

acid-catalysed cyclisation would provide access to benzomorphan related alkaloids.

We also proved that optically pure α,β-unsaturated lactams can be synthesised using this method,

by the synthesis of L-leucine-derived 171. Our initial probes into the directing effect of the

hydroxymethyl substituent showed that when a phenyl-substituted aziridine 180 was subjected to

our ring-opening conditions, the directing effect of the π(C–C)→σ*

(C–N) donation from the phenyl

ring led to only phenyl-directed ring-opening products being isolated 183.


120

2.2.15 Future Work

Having carried out initial studies into the synthesis of optically pure amino acid-derived lactams,

there remains scope to synthesise a series of amino acid-derived lactams, so that particularly

their 1,4-acid induced Michael-type cyclisations as well as Pictet–Spengler reactivity could be

assessed. This would provide a complementary lactam oxidation level alternative to the Craig

group’s previous tetrahydropyridine work. Of particular interest would be the synthesis of

tryptophan-derived 63 which would provide access to the indolomorphan motif following our

methodology.

Figure 46. Synthesis of optically pure lactams.

For the synthesis of macroline-related alkaloids, specifically the Michael-type addition of

β-ketoester 112, future preparations may seek to combine this addition with the formation of enol

triflate 161, by simply using KHMDS as the base for the Michael addition and then adding

N-phenyl-bis(trifluoromethanesulfonamide) to the potassium enolate product. This should

remove a step from the synthesis by producing enol triflate 161 in place of enol 91.

.


121

Figure 47. Revised one-pot synthesis of enol triflate 161.

Suggested conditions: a) KHMDS (1.5 equiv.), THF, −78°C→rt, 12 h, then Tf2NPh (2.0 equiv.), THF −78°C→rt, 16

h.

Having established a concise route to racemic alstonerine, the synthesis of optically pure

aziridine 93 (Figure 48, below) should provide rapid access to large quantities of

macroline-related alkaloids.65

This in turn could be applied to the synthesis of

bis(indole)alkaloids and sarpagine-related alkaloids as shown below. As an intermediate in our

racemic synthesis, optically pure aziridine 93 would provide naturally occurring (–)-alstonerine

in 12 steps (or 11 using the aforementioned revision of the synthesis of enol triflate 161), which

offers a significantly shorter route to those previously reported.

Figure 48. Known optically pure 93.

Due to the convergent nature of our synthesis, alkaloids containing indole oxidation could be

rapidly accessed, by using the equivalent methoxy substituted indole (Figure 49, below). For

example the synthesis of alstophylline 33 and in turn bis(indole) macralstonine 32 should be

readily achieved by introducing N1-methyl-6-methoxyindole 186 into our previous synthetic

route in the place of N1-methylindole.


122

Figure 49. Synthesis of bis(indole) alkaloid macralstonine 32.

Experimental

123

Chapter 3

Experimental

Experimental

124

3.1. General experimental procedures

Standard laboratory techniques were employed when handling air-sensitive reagents. All

reactions were performed under a nitrogen atmosphere unless otherwise stated. Melting points

were determined using a Stuart Scientific SMP1 or Büchi B-545 melting point apparatus and are

uncorrected. Infrared spectra were recorded on Perkin–Elmer Spectrum RX FT-IR or Spectrum

One FT-IR spectrometers. All 1H and

13C NMR spectra were recorded on a Bruker Ultra-Shield

AV-400 or AV-500 spectrometers. Chemical shifts (δH and δC) are expressed in parts per million

(ppm), referenced to the appropriate residual solvent peak. Mass spectra (CI, EI and FAB) were

recorded using a Micromass AutoSpec-Q, Micromass Platform II or Micromass AutoSpec

Premier spectrometer. Elemental analyses were performed at the microanalytical laboratories of

the London Metropolitan University. Thin-layer chromatography was performed on aluminium

plates pre-coated with silica gel (0.2 mm, Merck Kieselgel 60 F254), which were developed

using standard visualising agents: ultraviolet fluorescence (254 nm) and/or potassium

permanganate and/or vanillin. Chromatography refers to flash column chromatography

performed using BDH flash chromatography silica gel (40-63 µm) unless otherwise stated.

Standard solvents were distilled under nitrogen prior to use: THF was distilled from

sodiumbenzophenone ketyl, CH2Cl2, Et3N and Hünig’s base from CaH2 and MeOH from

Mg/MeOH. Hexane refers to the fraction of petroleum boiling between 67–70°C. All other

solvents and reagents were used as received from the supplier unless otherwise noted.

For the purposes of reporting NMR data, all compounds herein reported are numbered such that

the skeletal numbering corresponds to the final position of each carbon atom in the final natural

product, (±)-alstonerine 4 (Figure 50).

Figure 50. Compound numbering

Experimental

125

3.1.1 Procedures from the synthesis of hydroxymethyl-substituted aziridine 82

(Z)-4-(tert-Butyldimethylsilyloxy)but-2-en-1-ol (187)

To a suspension of 60 wt% NaH (22.2 g, 556.2 mmol, 0.98 equiv.) in THF (500 mL) at 0°C, was

added a solution of cis-but-2-ene-1,4-diol 92 (46.6 mL, 567.5 mmol, 1.0 equiv.) in THF (300

mL) slowly via dropping funnel. The resulting cloudy white suspension was allowed to stir

slowly from 0°C to rt overnight. The solution was then cooled to 0°C and a solution of TBSCl

(84.0 g, 556.2 mmol, 0.98 equiv.) in THF (300 mL) was added dropwise via dropping funnel and

the reaction mixture stirred at rt for 24 h.

The resulting creamy suspension was diluted with Et2O (500 mL) and poured onto ice cold

saturated aqueous NH4Cl (500 mL). The aqueous phase was extracted with Et2O (2×500 mL),

the combined organics dried over MgSO4, filtered and concentrated under reduced pressure.

Distillation under reduced pressure yielded (Z)-4-(tert-butyldimethylsilyloxy)but-2-en-1-ol 187

(110 g, 98%) as a colourless oil (b.p. 92–95°C at 2.4 mbar); Rf 0.51 (30% EtOAc–hexane); FTIR

(film) max: 3400, 2928, 2961, 2857, 1474, 1465, 1253, 1082, 1029, 833, 774 cm–1

; m/z (CI) 220

[M+NH4]+

, 203 [M+H]+ (Found [M+H]

+, 203.1465. C10H22O2Si requires [M+H]

+, 203.1467);

δH (400 MHz, CDCl3) 5.75––5.58 (2H, m, 5 and 16), 4.25 (2H, d, J 5.0 Hz, 6), 4.19 (2H, d, J 5.5

Hz, 17), 2.10 (1H, br. s, OH), 0.90 (9H, s, Me3CSi), 0.08 (6H, s, Me2Si);

δC (100 MHz, CDCl3) 131.1 (C5), 120.9 (C16), 59.6 (C6), 58.8 (C17), 25.7 (Me3CSi),

18.3 (Me3CSi), –5.3 (Me2Si). Data is in accordance with that previously reported.57

Experimental

126

((2R*,3S*)-3-((tert-Butyldimethylsilyloxy)methyl)-1-tosylaziridin-2-yl)methanol (93)

To a solution of olefin 187 (54.8 g, 270.9 mmol, 1.0 equiv.) and chloramine-T (91.6 g, 325.1

mmol, 1.2 equiv.) in MeCN (1300 mL) at rt was added PTAB (10.2 g, 27.0 mmol,

0.1 equiv.), and the resulting cloudy yellow suspension stirred at rt for 48 h. The reaction mixture

was concentrated under reduced pressure and the solid impurities triturated with Et2O (2×250

mL). The residue was filtered, (washing with Et2O) and concentrated under reduced pressure.

Chromatography (30% EtOAc–hexane) yielded ((2R*,3S*)-3-((tert-

butyldimethylsilyloxy)methyl)-1-tosylaziridin-2-yl)methanol 93 (72.4 g, 76%) as a colourless oil;

Rf 0.61 (50% EtOAc–heptane); FTIR (film) max: 3500, 2933, 2861, 1601, 1466, 1324, 1264,

1159, 1089, 948, 834, 669 cm–1

; m/z (CI) 372 [M+H]+ (Found [M+H]

+, 372.1431. C17H29NO4SSi

requires [M+H]+, 372.1587);

δH (400 MHz, CDCl3) 7.82 (2H, app. d, J 8.0 Hz, ortho-Ts), 7.33 (2H, app. d, J 8.0 Hz,

meta-Ts), 3.91 (1H, dd, J 11.5, 5.5 Hz, 5), 3.79––3.55 (3H, m, 16, 6a and 6b), 3.09 (2H, dt, J

30.0, 14.5 Hz, 17a and 17b), 2.45 (3H, s, TsMe), 0.87 (9H, s, Me3CSi), 0.05 (3H, s, Me2Si), 0.04

(3H, s, Me2Si);

δC (100 MHz, CDCl3) 135.3 (para-Ts) 134.5 (ipso-Ts), 129.8 (ortho-Ts), 128.0 (meta-Ts), 60.38

(C6), 59.2 (C17), 44.0 (C5), 42.9 (C16), 25.7 (Me3CSi), 21.4 (TsMe), 18.2 (Me3CSi),

–5.5 (Me2Si). Data is in accordance with that previously reported.57

Experimental

127

N-((R*)-2-(tert-Butyldimethylsilyloxy)-1-((S*)-oxiran-2-yl)ethyl)-4-

methylbenzenesulfonamide (94)

To a suspension of 60 wt% NaH in mineral oil (35.7 g, 643.8 mmol, 4.0 equiv.) in THF (300

mL) at 0°C was added dropwise, a solution of aziridine 93 (59.8 g, 160.9 mmol, 1.0 equiv.) over

30 min. The reaction mixture was stirred at 0°C for 4 h then cooled to –78°C and saturated

aqueous NH4Cl solution (250 mL) added dropwise. On warming to rt, the aqueous layer was

extracted with Et2O (2×300 mL), the combined organics dried over MgSO4 and filtered.

Concentration under reduced pressure and chromatography

(30% EtOAc–heptane) yielded N-((R*)-2-(tert-butyldimethylsilyloxy)-1-((S*)-oxiran-2-yl)ethyl)-

4-methylbenzenesulfonamide 94 (56.2 g, 94%) as a colourless oil; Rf 0.51 (30% EtOAc–hexane);

FTIR (film) max: 2928, 2857, 1600, 1474, 1336, 1253, 1163, 1092, 899, 836, 814 cm–1;

m/z (CI)

372 [M+H]+ (Found [M+H]

+, 372.1667. C17H29NO4SSi requires [M+H]

+, 372.1587);


meta-Ts), 4.72 (1H, d, J 8.0 Hz, N4HTs), 3.60––3.46 (3H, m, 16, 17a and 17b), 3.17––3.14 (1H,

m, 5), 2.66 (1H, dd, J 4.5, 4.0 Hz, 6a), 2.57 (1H, dd, J 4.5, 3.0 Hz, 6b), 2.45 (3H, s, TsMe), 0.87

(9H, s, Me3CSi), 0.02 (6H, s, Me2Si);

δC (100 MHz, CDCl3) 144.8 (para-Ts) 134.5 (ipso-Ts), 129.8 (meta-Ts), 128.0 (ortho-Ts), 60.3

(C17), 59.5 (C16), 51.2 (C5), 43.4 (C6), 25.7 (Me3CSi), 21.7 (TsMe), 18.2 (Me3CSi),

–5.5 (Me2Si). Data is in accordance with that previously reported.57

Experimental

128

N-((2R*,3R*)-1-(tert-Butyldimethylsilyloxy)-3-hydroxy-4-(1-methylindol-3-yl)butan-2-yl)-4-


To a suspension of epoxide 94 (7.00 g, 18.84 mmol, 1.0 equiv.), 1-methylindole

(4.70 mL, 37.68 mmol, 2.0 equiv.) and anhydrous NaHCO3 (6.33 g, 75.36 mmol, 4.0 equiv.) in

CH2Cl2 (50 mL) at –78°C was added BF3·OEt2 (2.56 mL, 20.78 mmol, 1.1 equiv.) dropwise and

the reaction mixture was stirred at –78°C for 6 h. Water (20 mL) was added slowly and the

resulting suspension allowed to warm from –78°C to rt. The aqueous layer was extracted with

Et2O (3×50 mL), the combined organics dried over Na2SO4 and filtered. Concentration under

reduced pressure and chromatography (33% EtOAc–hexane) yielded N-((2R*,3R*)-1-(tert-

butyldimethylsilyloxy)-3-hydroxy-4-(1-methylindol-3-yl)butan-2-yl)-4-methylbenzenesulfonamide

95 (8.61 g, 94%) as a colourless amorphous solid; Rf 0.24 (33% EtOAc–hexane); FTIR (film)

max: 3507, 3288, 2954, 2929, 2857, 1616, 1474, 1330, 1160, 1092, 1073, 838, 734 cm–1

; m/z

(CI) 520 [M+NH4]+, 503 [M+H]

+ (Found [M+H]

+, 503.2322. C26H38N2O4SSi requires [M+H]

+,

503.2415);

δH (400 MHz, CDCl3) 7.78 (2H, app. d, J 8.0 Hz, ortho-Ts), 7.48 (1H, d, J 8.0 Hz, 12),

7.33––7.24 (3H, m, 9 and meta-Ts), 7.22 (1H, t, J 7.5 Hz, 11), 7.09 (1H, t, J 7.5 Hz, 10), 6.66

(1H, s, 2), 5.32 (1H, d, J 9.0 Hz, N4HTs), 4.24 (1H, t, J 6.5 Hz, 5), 3.73 (3H, s, N1Me), 3.68 (1H,

dd, J 10.0, 5.0 Hz, 17a), 3.63 (1H, dd, J 10.0, 3.0 Hz, 17b), 3.41––3.34 (1H, m, 16), 2.76 (2H,

qd, J 11.0, 7.0 Hz, 6a and 6b), 2.45 (3H, s, TsMe) 0.88 (9H, s, Me3CSi), –0.01 (6H, s, Me2Si);

δC (100 MHz, CDCl3) 143.4 (para-Ts), 138.7 (ipso-Ts), 137.1 (C13), 129.9 (ortho-Ts), 128.0

(meta-Ts), 127.7 (C2), 127.3 (C8), 121.8 (C11), 119.0 (C10), 119.0 (C12), 110.0 (C9), 109.3

(C7), 72.1 (C5), 65.7 (C17), 55.4 (C16), 32.6 (N1Me), 29.5 (C6), 25.8 (Me3CSi), 21.5 (TsMe),

18.1 (Me3CSi), –5.7 (Me2Si). Data is in accordance with that previously reported.57

Experimental

129

3-(((2S*,3S*)-3-((tert-Butyldimethylsilyloxy)methyl)-1-tosylaziridin-2-yl)methyl)-1-

methylindole (96)

To a solution of hydroxysulfonamide 95 (7.10 g, 14.12 mmol, 1.0 equiv.) and Ph3P (4.45 g,

16.95 mmol, 1.2 equiv.) in THF (150 mL) at rt was added DIAD (4.20 mL, 21.19 mmol, 1.5

equiv.) dropwise and the reaction mixture stirred at rt for 16 h. Concentration under reduced

pressure and chromatography (30% EtOAc–hexane) yielded 3-(((2S*,3S*)-3-((tert-

butyldimethylsilyloxy)methyl)-1-tosylaziridin-2-yl)methyl)-1-methylindole 96 (5.91 g, 86%) as a

pale yellow oil; Rf 0.44 (20% EtOAc–hexane); FTIR (film) max: 2953, 2929, 2884, 1725, 1598,

1474, 1330, 1160, 1122 838, 734 cm–1

; m/z (CI) 485 [M+H]+ (Found [M+H]

+, 485.2309.

C26H36N2O3SSi requires [M+H]+, 485.2294);

δH (400 MHz, CDCl3) 7.64 (2H, d, J 8.0 Hz, ortho-Ts), 7.48 (1H, d, J 8.0 Hz, 12),

7.27––7.20 (2H, m, 9 and 11), 7.12 (2H, d, J 8.0 Hz, meta-Ts), 7.13––7.06 (1H, m, 10), 6.85

(1H, s, 2), 3.90 (1H, dd, J 11.0, 5.5 Hz, 17a), 3.78 (1H, dd, J 11.0, 6.5 Hz, 17b), 3.68 (3H, s,

N1Me), 3.18 (1H, app. q, J 6.5 Hz, 16), 3.11 (1H, app. q, J 6.5 Hz 5), 2.99 (1H, dd J 15.5, 5.5

Hz, 6a), 2.89 (1H, dd J 15.5, 7.5 Hz, 6b), 2.40 (3H, s, TsMe), 0.88 (9H, s, Me3CSi), 0.04 (6H, s,

Me2Si);


(meta-Ts), 127.5 (C2), 126.9 (C8), 121.6 (C11), 118.9 (C10), 118.6 (C12), 110.1 (C9), 109.1

(C7), 60.3 (C17), 44.8 (C5), 44.6 (C16), 32.6 (N1Me), 25.9 (Me3CSi), 22.9 (C6), 21.6 (TsMe),

(Me3CSi), –5.53 (Me2Si). Data is in accordance with that previously reported.57

Experimental

130

((2S*,3S*)-3-((1-Methylindol-3-yl)methyl)-1-tosylaziridin-2-yl)methanol (82)

To a solution of O-TBS protected aziridine 96 (5.90 g, 12.17 mmol, 1.0 equiv.) in THF (50 mL)

at 0°C was added TBAF·3H2O (4.22 g, 13.39 mmol, 1.1 equiv.) and the reaction mixture

allowed to warm slowly from 0°C to rt overnight. Saturated aqueous NH4Cl (2 mL) was added,

the aqueous layer extracted with CH2Cl2 (3×50 mL), the combined organics dried over Na2SO4

and filtered. Concentration under reduced pressure and chromatography (50% EtOAc–hexane)

yielded ((2S*,3S*)-3-((1-methylindol-3-yl)methyl)-1-tosylaziridin-2-yl)methanol 82 (4.28 g,

95%) as a pale yellow oil; Rf 0.31 (50% EtOAc–hexane); FTIR (film) max: 3508, 3364, 2933,

1810, 1783, 1598, 1325, 1184, 1091, 739 cm–1

; m/z (CI) 371 [M+H]+ (Found [M+H]

+, 371.1351.

C20H22N2O3S requires [M+H]+, 371.1351);


7.27––7.20 (2H, m, 9 and 11), 7.12 (2H, app. d, J 8.0 Hz, meta-Ts), 7.12––7.06 (1H, m, 10),

6.78 (1H, s, 2), 3.90 (1H, ddd, J 11.0, 7.5, 5.5 Hz, 17a), 3.78 (1H, dd, J 11.0, 6.5 Hz, 17b), 3.68

(3H, s, N1Me), 3.18 (1H, app. q, J 6.5 Hz, 5), 3.11 (1H, app. q, J 6.5 Hz, 16), 2.99 (1H, dd, J

15.5, 5.5 Hz, 6a), 2.89 (1H, dd, J 15.5, 7.5 Hz 6b), 2.40 (3H, s, TsMe);


(meta-Ts), 127.8 (C2), 127.3 (C8), 121.7 (C11), 119.0 (C10), 118.5 (C12), 109.9 (C9), 109.2

(C7), 62.4 (C17), 45.5 (C5), 43.8 (C16), 32.7 (N1Me), 22.9 (C6), 21.6 (TsMe). Data is in

accordance with that previously reported.67

Experimental

131

3.1.2 Procedures from the synthesis of sulfone 88

Phenyl vinyl sulfide (97)

To ethanol (400 mL) in a 1 L three-necked round-bottomed flask fitted with a condenser was

added sodium metal (23 g, 1000 mmol, 1.0 equiv.) in small pieces. Once the sodium had

dissolved, benzenethiol (102 mL, 1000 mmol, 1.0 equiv.) was added via dropping funnel. The

resulting solution was then transferred via cannula into a 2 L three-necked round-bottomed flask

containing a stirred solution of 1,2-dibromoethane (124 mL, 1450 mmol, 1.45 equiv.)

in ethanol (28 mL) dropwise over 45 min. The reaction temperature was maintained at 25–30°C

throughout the addition. The resulting slurry was then allowed to stir at rt for 30 min, before

ethanolic sodium ethoxide prepared from dissolving sodium (40 g, 1740 mmol, 1.74 equiv.) in

ethanol (800 mL) was added and the reaction mixture stirred under reflux for 8 h. The reaction

mixture was then cooled, before toluene (750 mL) and water (750 mL) were added. The

aquesous layer was extracted with toluene (3×500 mL) and the organics phases were combined,

washed with water (2×50 mL) and brine (100 mL). Concentrated under reduced pressure and

distillation gave phenyl vinyl sulphide 97 (92.6 g, 68%) as a colourless oil; (b.p. 93°C at 33.3

mbar); Data is in accordance with that previously reported.75

Experimental

132

(2,2-Dichlorocyclopropylsulfonyl)benzene (99)

To a slurry of freshly prepared sodium methoxide (15.9 g, 293.7 mmol, 2.0 equiv.) and phenyl

vinyl sulfide 97 (20.0 g, 146.8 mmol, 1.0 equiv.) in CH2Cl2 (500 mL) at –78°C was added

dropwise via dropping funnel ethyl trichloroacetate (30.5 mL, 220.2 mmol, 1.5 equiv.) and the

solution allowed to warm slowly from –78°C to rt over 6 h. H2O (300 mL) was then added, and

the aqueous layer extracted with CH2Cl2 (3×300 mL), dried over MgSO4 and filtered.

Concentration under reduced pressure yielded crude intermediate (2,2-

dichlorocyclopropyl)phenylsulfide 98 as a dark brown oil.

To a solution of crude intermediate (2,2-dichlorocyclopropyl)phenylsulfide 98 (47.8 g, 219.3

mmol, 1.0 equiv.) and AcOH (354 mL, 5886 mmol, ~25 equiv.) was added aqueous 30% H2O2

solution (103 mL, 907 mmol, ~4.0 equiv.) dropwise. The solution was then stirred under reflux

at 100°C for 4 h, after which the reaction mixture was partitioned over Et2O (3×500 mL),

neutralised with K2CO3, washed with brine (500 mL) and filtered over a pad of silica.

Concentration under reduced pressure and flash column chromatography (30% EtOAc–hexane)

yielded (2,2-dichlorocyclopropylsulfonyl)benzene 99 (33.4 g, 91%, over two steps) as a

crystalline solid; Rf 0.45 (50% EtOAc–hexane); m.p. = 88°C (lit.72,73,74

m.p. 87–88°C); max

(film) 3112, 3033, 1446, 1322, 1214, 1158, 1087, 723 cm–1

; m/z (CI) 268 [M+NH4]

+ (Found

[M+NH4]+, 267.9970. C9H8Cl2O2S requires [M+H]

+, 267.9966);

δH (400 MHz, CDCl3) 8.01 (2H, d, J 8.0 Hz, ortho-PhSO2), 7.73 (1H, t, J 8.0 Hz, para-PhSO2),

7.62 (2H, t, J 8.0 Hz, meta-PhSO2), 3.20 (1H, dd, J 10.5, 2.5 Hz, 14a), 2.45 (1H, t, J 8.0 Hz, 15),

2.17 (1H, dd, J 10.5, 2.5 Hz, 14b);

δC (100 MHz, CDCl3) 139.6 (para-PhSO2), 134.3 (ipso-PhSO2), 129.5 (ortho-PhSO2), 128.1

(meta-PhSO2), 55.4 (C3), 47.9 (C15), 26.3 (C14). Data is in accordance with that previously

reported.72,73,74

Experimental

133

(2,2-Dichlorocyclopropylsulfonyl)benzene (99) – Small Scale Prep.

Sodium metal (63.30 mg, 27.53 mmol, 1.5 equiv.) was dissolved in dry methanol (10 mL).

Concentration under reduced pressure yielded sodium methoxide (1.49 g, 27.53 mmol, 1.5

equiv.), to which was added olefin-free petrol80

(14 mL) and phenyl vinyl sulphide 97 (2.4 mL,

18.35 mmol, 1.0 equiv.) and the reaction mixture cooled to – 20°C. Ethyl trichloroacetate (3.3

mL, 23.86 mmol, 1.3 equiv.) was added at a rate of 6 mL / min via syringe pump addition, and

the reaction mixture stirred at – 20°C for 6 h, before being allowed to warm to rt slowly

overnight. H2O (30 mL) was then added, and the aqueous layer extracted with CH2Cl2 (3×30

mL), dried over MgSO4 and filtered. Concentration under reduced pressure and distillation

yielded crude intermediate compound 98 (5.16 g) as a dark brown oil.

To a solution of crude intermediate 98 (10.05g, 45.86 mmol, 1.0 equiv.) and AcOH (70 mL,

1177 mmol, 25 equiv.) was added 30% H2O2 solution (20.5 mL, 181.5 mmol, 4.0 equiv.)

dropwise. The solution was then stirred under reflux at 100°C for 3 h, after which the reaction

mixture was partitioned over Et2O (3×100 mL), neutralised with K2CO3 over, washed with brine

(100 mL) and filtered. Concentration under reduced pressure and flash column chromatography

(30% EtOAc–hexane) yielded (2,2-dichlorocyclopropylsulfonyl)benzene 99 (7.74 g, 84%, over

two steps) as a crystalline solid;

N.B. For the original synthesis of 98 (as outlined in Scheme 26), see the thesis of Tholen.57

Experimental

134

Trimethyl 3-(phenylsulfonyl)orthopropionate (88)

To dry MeOH (200 mL) at 0°C was added sodium (3.68 g, 153.3 mmol, 3.5 equiv.) portionwise.

Following formation of in situ sodium methoxide, dichloro-sulfone 99 (11.0 g, 43.80 mmol, 1.0

equiv.) in MeOH (100 mL) was added and the reaction mixture stirred under reflux at 65°C for 3

h, cooled to rt and concentrated under reduced pressure. The concentrate was then partitioned

over H2O (200 mL) and Et2O (200 mL), and the aqueous layer extracted with Et2O (3×300 mL).

The organic phases were combined, dried over NaSO4, and filtered. Concentration under reduced

pressure and chromatography yielded trimethyl 3-(phenylsulfonyl)orthopropionate 88 (11.8,

98%) as a colourless oil; Rf 0.50 (66% EtOAc–hexane); max (film) 2947, 2840, 1446, 1284,

1240, 1143, 1076, 100 cm–1

; m/z (CI) 292 [M+NH4]

+ (Found [M+NH4]

+, 292.1219. C12H18O5S

requires [M+NH4]+, 292.1219);

δH (400 MHz, CDCl3) 7.90 (2H, d, J 8.5 Hz, ortho-PhSO2), 7.67 (1H, t, J 7.5 Hz, para-PhSO2),

7.58 (2H, t, J 7.5 Hz, meta-PhSO2), 3.17 (9H, s, 3×OMe), 3.13 (2H, dt, J 16.5, 4.0 Hz, 15), 2.17

(2H, dt, J 16.5, 4.0 Hz, 14);

δC (100 MHz, CDCl3) 138.9 (para-PhSO2), 134.1 (ipso-PhSO2), 129.4 (ortho-PhSO2), 128.1

(meta-PhSO2), 114.28 (C3), 51.4 (OMe), 49.6 (C15), 23.9 (C14). Data is in accordance with

that previously reported.72,73,74

Experimental

135

3.1.3 Procedures from sulfone stability and aziridine reactivity (Sections 2.1.7-2.1.9)

Methyl 3-(phenylsulfonyl)propanoate (101)

To a solution of orthoester 88 (30 mg, 0.109 mmol, 1.0 equiv.) in THF (2 mL) was added

aqueous HCl (2 M; 0.5 mL, 1.00 mmol, 10 equiv.) and the solution stirred at rt overnight.

Saturated aqueous NH4Cl (5 mL) was added, and the aqueous layer extracted with EtOAc (3×20

mL). The organic layers were combined, washed with brine, dried over MgSO4, and filtered.

Concentration under reduced pressure yielded methyl 3-(phenylsulfonyl)propanoate 101 (24.1

mg, 97%) as a colourless amorphous solid; Rf 0.51 (30% EtOAc–hexane); max (film) 2955,

1736, 1586, 1586, 1447, 1439, 1148, cm–1

; m/z (CI) 246 [M+NH4]+, 229 [M+H]

+.

δH (400 MHz, CDCl3) 7.92 (2H, app. d, J 7.5 Hz, ortho-PhSO2), 7.69 (1H, t, J 7.5 Hz, para-

PhSO2), 7.58 (2H, t, J 7.5 Hz, meta-PhSO2), 3.64 (3H, s, OMe), 3.44 (2H, t, J 7.5 Hz, 15), 2.79

(2H, t, J 7.5 Hz, 14);

δC (100 MHz, CDCl3) 170.5 (C3), 138.4 (ipso-PhSO2), 134.1 (para-PhSO2), 129.5

(ortho-PhSO2), 128.2 (meta-PhSO2), 52.3 (C15), 51.5 (OMe), 27.6 (C14). Data is in accordance

with that previously reported.57

Experimental

136

N-((2S*,3R*)-4-Hydroxy-1-(1-methylindol-3-yl)-3-(phenylsulfonylmethyl)butan-2-yl)-4-


To a solution of methyl phenyl sulfone 105 (165.3 mg, 1.058 mmol, 2.5 equiv.) in THF (0.5 mL)

at –40°C was added n-BuLi (2.48 M in hexanes; 0.44 mL, 1.058 mmol, 2.5 equiv.) and the

solution stirred at –40°C for 30 min. A solution of hydroxymethyl-aziridine 82 (0.85 M in THF;

0.5 mL, 0.423 mmol, 1.0 equiv.) was added and the reaction mixture stirred at –40°C for 2 h.

10% Aqueous citric acid (1 mL) was added and the aqueous layer extracted with EtOAc (3×10

mL). The combined organics layers were washed with brine, dried over MgSO4 and filtered.

Concentration under reduced pressure and chromatography (20% EtOAc–hexane) yielded

N-((2S*,3R*)-4-hydroxy-1-(1-methylindol-3-yl)-3-(phenylsulfonylmethyl)butan-2-yl)-4-

methylbenzenesulfonamide 107 (162.0 mg, 73%) as a colourless oil; Rf 0.35 (50% EtOAc–

hexane); FTIR (film) max: 3505, 3299, 3054, 2928, 1598, 1447, 1304, 1152 cm–1

; m/z (CI) 527

[M+H]+ (Found [M+H]

+, 527.1667. C27H30N2O5S2 requires [M+H]

+, 527.1597);

δH (400 MHz, CDCl3) 7.92 (2H, app. d, J 7.5 Hz, ortho-PhSO2), 7.60 (1H, t, J 7.5 Hz,

para-PhSO2), 7.50 (2H, t, J 7.5 Hz, meta-PhSO2), 7.45 (2H, app. d, J 8.0 Hz, ortho-Ts),

7.19––7.06 (3H, m, 12, 11 and 9), 7.00––6.91 (3H, m, meta-Ts and 10), 6.69 (1H, s, 2), 5.52

(1H, d, J 7.5 Hz, N4HTs), 3.84 (2H, m, 17a and 17b), 3.73 (1H, m, 5), 3.56 (3H, s, N1Me), 3.40

(1H, dd, J 15.0, 4.5 Hz, 15a), 3.27 (1H, dd, J 15.0, 7.0 Hz, 15b), 2.97 (1H, br. s, OH), 2.83

(1H, dd, J 15.0, 6.5 Hz, 6a), 2.70 (1H, dd, J 15.0, 8.0 Hz, 6b), 2.53 (1H, br. m, 16), 2.31 (3H, s,

TsMe);

δC (400 MHz, CDCl3) 143.1 (para-Ts), 139.2 (para-PhSO2), 136.9 (C13), 136.6 (ipso-Ts),

133.9 (ipso-PhSO2), 129.4 (ortho-PhSO2), 129.2 (meta-Ts), 128.0 (meta-PhSO2), 127.4 (C8),

126.7 (ortho-Ts), 126.6 (C2), 121.5 (C11), 119.0 (C10), 118.4 (C12), 109.2 (C9), 108.7 (C7),

62.5 (C17), 54.4 (C15), 53.7 (C5), 39.3 (C16), 32.5 (N1Me), 28.3 (C6), 21.6 (TsMe).

Experimental

137

4-Methyl-N-((S*)-2-(1-methylindol-3-yl)-1-((R*)-oxiran-2-yl)ethyl)benzenesulfonamide

(106)

To a suspension of 60 wt% NaH in mineral oil (86.30 mg, 2.158 mmol, 3.0 equiv.) in THF

(1 mL) at 0°C was added via cannula, a solution of hydroxymethyl-aziridine 82 (260 mg, 0.719

mmol, 1.0 equiv.). The reaction mixture was allowed to warm slowly from 0°C to rt over 5 h,

cooled to 0°C and saturated aqueous NH4Cl (5 mL) added dropwise. On warming to rt, the

aqueous layer was extracted with EtOAc (3×12 mL) and the combined organics were dried over

MgSO4. Concentration of the filtrate under reduced pressure and flash column chromatography

(20% EtOAc–hexane) yielded 4-methyl-N-((S*)-2-(1-methylindol-3-yl)-1-((R*)-oxiran-2-

yl)ethyl)benzenesulfonamide 106 (66.5 mg, 77%) as a colourless gum; Rf 0.51

(20% EtOAc–hexane); FTIR (film) max: 2928, 2857, 1600, 1474, 1336, 1253, 1163, 1092, 899,

836, 814 cm–1;

m/z (CI) 371 [M+H]+ (Found [M+H]

+, 371.1351. C20H22N2O3S requires [M+H]

+,

371.1351);

δH (400 MHz, CDCl3) 7.56 (2H, app. d, J 8.0 Hz, ortho-Ts), 7.33 (1H, app. d, J 8.0 Hz, 9),

7.24––7.18 (2H, m, 12 and 11), 7.11 (2H, app. d, J 8.0 Hz, meta-Ts), 7.06 (1H, dt, J 8.0, 2.0 Hz,

10), 6.81 (1H, s, 2), 4.70 (1H, d, J 8.0 Hz, N4HTs), 3.78 (1H, dt, J 8.0, 2.0 Hz, 5), 3.68 (3H, s,

N1Me), 3.09 (1H, dt, J 4.0, 2.0 Hz, 16), 3.03––2.89 (2H, m, 6a and 6b), 2.74 (1H, dd, J 4.5, 4.0

Hz, 17a), 2.68 (1H, t, J 4.5 Hz, 17b), 2.37 (3H, s, TsMe);


(C2), 127.6 (C8), 126.8 (meta-Ts) 121.7 (C11), 119.1 (C10), 118.6 (C12), 109.3 (C9), 108.9

(C7), 53.0 (C17), 52.9 (C16), 44.8 (C5), 32.7 (N1Me), 29.5 (C6), 21.6 (TsMe).

Experimental

138

3.1.4 Procedures from initial work towards the synthesis of key intermediate lactam–alcohol 90

(Sections 2.1.6-2.1.13)

(3R*,4R*,5S*)-Methyl 4-(hydroxymethyl)-6-(1-methylindol-3-yl)-5-(4-

methylphenylsulfonamido)-3-(phenylsulfonyl)hexanoate (89)

To a solution of trimethyl 3-(phenylsulfonyl)orthopropionate 88 (141.8 mg, 0.518 mmol, 2.5

equiv.) in THF (2 mL) at –40°C was added n-BuLi (2.48 M in hexanes; 0.27 mL,

0.673 mmol, 3.3 equiv.) and the solution stirred for 1 h at –40°C.

Meanwhile, n-BuLi (2.48 M in hexanes; 0.1 mL, 0.227 mmol, 1.1 equiv.) was added to a

solution of hydroxymethyl-aziridine 82 (76.5 mg, 0.207 mmol, 1.0 equiv.) in THF (1 mL) at

–40°C and the solution stirred for 1 h at –40°C.

The dark red solution of deprotonated 88 was added dropwise via cannula to the dark green

solution of O-lithio hydroxymethyl-aziridine 82, maintaining both solutions at –40°C throughout

the addition. The reaction mixture was allowed to warm slowly from –40°C to rt overnight.

Aqueous 10% citric acid (1 mL) was added and the solution stirred for 3 h at rt. The aqueous

layer was then extracted with EtOAc (3×30 mL) and CH2Cl2 (3×30 mL), the organic layers

combined, dried over MgSO4 and filtered. Concentration under reduced pressure and flash

column chromatography (20% EtOAc–hexane) yielded (3R*,4R*,5S*)-methyl 4-

(hydroxymethyl)-6-(1-methylindol-3-yl)-5-(4-methylphenylsulfonamido)-3-

(phenylsulfonyl)hexanoate 89 (33.4 mg, 27%) as an amorphous solid; Rf 0.16 (66% EtOAc–

hexane); FTIR (film) max: 3528, 3305, 3060, 2952, 1738, 1156 cm–1

; m/z (CI) 599 [M+H]+

(Found [M+H]+, 599.1862. C30H34N2O7S2 requires [M+H]

+, 599.1870);

δH (400 MHz, CDCl3) 7.92 (2H, d, J 8.0 Hz, ortho-PhSO2), 7.70––7.63 (1H, m, 11), 7.60––7.53

(3H, m, meta-PhSO2 and para-PhSO2), 7.24––7.15 (2H, m, ortho-Ts and 12), 7.07 (2H, d, J 8.0

Experimental

139

Hz, meta-Ts), 7.04––6.94 (2H, m, 10 and 9), 6.80 (1H, s, 2), 5.84 (1H, d, J 9.0 Hz, N4HTs), 4.32

(1H, dt, J 3.0, 6.0 Hz, 15), 4.14––3.88 (3H, 5 and 17), 3.64 (3H, s, N1Me), 3.40 (3H, s, OMe),

3.07 (2H, dd, J 14.5, 7.0 Hz, 6), 2.93––2.81 (2H, m, 14), 2.54––2.46 (1H, m, 16), 2.37 (3H, s,

TsMe);

δC (100 MHz, CDCl3); 170.7 (C3), 142.9 (para-Ts), 137.8 (ipso-PhSO2), 137.6 (ipso-Ts), 134.2

(C13), 129.8 (ortho-Ts), 129.3 (ortho-PhSO2), 129.2 (meta-Ts), 129.0 (meta-PhSO2), 128.8

(ortho-PhSO2), 127.7 (C2), 126.8 (ortho-Ts), 121.7 (C11), 119.1 (C10), 118.5 (C12), 109.0

(C9), 107.5 (C7), 60.1 (C17), 59.2 (OMe), 53.2 (C15), 52.2 (C5), 46.8 (C16), 34.1 (C14), 32.5

(N1Me), 29.0 (C6), 21.6 (TsMe). Data is in accordance with that previously reported.57

(3R*,4R*,5S*)-Methyl 4-((tert-butyldimethylsilyloxy)methyl)-6-(1-methylindol-3-yl)-5-(4-

methylphenylsulfonamido)-3-(phenylsulfonyl)hexanoate (102a) – Small Scale Original Prep.

To a stirred solution of amino alcohol 89 (96.5 mg, 0.161 mmol,

1.0 equiv.), imidazole (16.0 mg, 0.242 mmol, 1.5 equiv.) and TBSCl (36.5 mg, 0.242 mmol, 1.5

equiv.) in DMF (0.2 mL) was added DMAP (2.0 mg, 0.016 mmol, 10 mol%) and the reaction

mixture stirred at rt for 3 h. H2O (1 mL) was added and the reaction mixture was poured onto

aqueous 10% citric acid. The aqueous layer was extracted with EtOAc (3×10 mL) and the

organic phases combined, washed with brine, dried over MgSO4 and filtered. Concentration

under reduced pressure and chromatography (33% EtOAc–hexane) yielded

(3R*,4R*,5S*)-methyl 4-((tert-butyldimethylsilyloxy)methyl)-6-(1-methylindol-3-yl)-5-(4-

methylphenylsulfonamido)-3-(phenylsulfonyl)hexanoate 102a (56.1 mg, 49%) as a pale yellow

oil; Rf 0.90 (66% EtOAc–hexane); FTIR (film) max: 2928, 2859, 1742, 1156 cm–1

; m/z (CI) 713

Experimental

140

[M+H]+ (Found [M+H]

+, 713.2740. C36H48N2O7S2Si requires [M+H]

+, 713.2672). For data,

please refer to O-TBS ring-opening reaction (Page 143).

(5R*,6S*)-5-((tert-Butyldimethylsilyloxy)methyl)-6-((1-methylindol-3-yl)methyl)-1-tosyl-

5,6-dihydropyridin-2(1H)-one (104) – Small Scale Original Prep.

To a stirred solution of O-TBS protected amino alcohol 102a (32.9 mg, 0.046 mmol, 1.0 equiv.)

in toluene (1 mL) was added trimethylaluminium (2.0 M in hexane; 26 μL, 0.051 mmol, 1.1

equiv.) and the solution stirred at rt for 30 min. After 30 min at rt, the reaction mixture was

heated to 80°C for 3 h and cooled to rt. Saturated aqueous NH4Cl

(1 mL) was added and the aqueous layer extracted with EtOAc (3×10 mL). The organic phases

were combined, washed with brine, dried over MgSO4 and filtered. Concentration under reduced

pressure and chromatography (33% EtOAc–hexane) yielded (5R*,6S*)-5-((tert-

butyldimethylsilyloxy)methyl)-6-((1-methylindol-3-yl)methyl)-1-tosyl-5,6-dihydropyridin-2(1H)-

one 104 (56.1 mg, 49%) as a pale yellow oil; Rf 0.65 (33% EtOAc–hexane); FTIR (film) max:

3050, 2953, 2856, 1687 cm–1

; m/z (CI) 538 [M+H]+ (Found [M+H]

+, 538.2383. C29H38N2O4SSi

requires [M+H]+, 539.2322).

δH (400 MHz, CDCl3) 8.01 (2H, app. d, J 8.0 Hz, ortho-Ts) 7.69 (1H, d, J 8.0 Hz, 9),

7.33––7.18 (3H, m, 12 and meta-Ts), 7.24 (1H, t, J 8.0 Hz, 11), 7.14 (1H, t, J 8.0 Hz, 10), 6.92

(1H, s, 2), 6.50 (1H, ddd, J 10.0, 6.0, 1.5 Hz, 15), 5.90 (1H, d, J 10.0 Hz, 14), 5.21 (1H, dd, J

11.5, 4.0 Hz, 5), 3.75 (3H, s, N1Me), 3.45 (1H, dd, J 10.0, 5.5 Hz, 17a), 3.33 (1H, dt, J 10.0, 4.0

Hz, 17b) 3.26 (1H, t, J 14.0 Hz, 6a), 3.14 (1H, dd, J 14.0, 12.0 Hz, 6b), 2.65 (1H, dt, J 10.0, 5.5

Hz, 16), 2.42 (3H, s, TsMe), 0.77 (9H, s, Me3CSi), –0.05 (3H, s, MeSi),–0.19 (3H, s, MeSi);

Experimental

141

δC (100 MHz, CDCl3) 161.6 (C3), 145.0 (para-Ts), 142.4 (C15), 137.2 (C13), 136.6 (ipso-Ts),

129.7 (meta-Ts), 129.4 (ortho-Ts), 127.9 (C2), 127.5 (C8), 125.7 (C14), 122.0 (C11), 119.5

(C10), 119.1 (C12), 109.5 (C7), 109.3 (C9), 62.9 (C17), 56.9 (C5), 39.8 (C16), 32.9 (N1Me),

30.1 (C6), 25.9 (Me3CSi), 21.7 (TsMe), 18.0 (Me3CSi), –5.6 (Me2CSi)2. Data is in accordance

with that previously reported.57

(5R*,6S*)-5-(Hydroxymethyl)-6-((1-methylindol-3-yl)methyl)-1-tosyl-5,6-dihydropyridin-

2(1H)-one (90) – Small Scale Original Prep.

To a stirred solution of O-TBS protected lactam 104 (32.9 mg, 0.046 mmol, 1.0 equiv.) in THF

(1 mL) at rt was added AcOH:H2O (1 mL:1 mL) and the reaction mixture stirred at rt for 30 h.

Water (1 mL) was added and the aqueous layer extracted with EtOAc (3×10 mL). The organic

phases were combined, washed with brine, dried over MgSO4 and filtered. Concentration under

reduced pressure and chromatography (66% EtOAc–hexane) yielded (5R*,6S*)-5-

(hydroxymethyl)-6-(1-methylindol-3-yl)methyl)-1-(4-methylphenylsulfonamido)-5,6-

dihydropyridine-2(1H)-one 90 (20.3 mg, 65%) as an amorphous solid; Rf 0.25 (66% EtOAc–

hexane); For data, please refer to the final approach to alstonerine (Page 153).

Experimental

142

Procedure for ring-opening of OTBS-hydroxymethyl-substituted aziridine (96)

To a solution of trimethyl 3-(phenylsulfonyl)orthopropionate 88 (1.90 g, 6.93 mmol, 1.8 equiv.)

in THF (2 mL) at –78°C was added n-BuLi (2.44 M in hexanes; 3.3 mL, 8.05 mmol, 2.0 equiv.)

and the solution stirred for 1 h at –78°C.

The dark red solution of deprotonated 88 was then added dropwise via cannula to a solution of

O-TBS hydroxymethyl-aziridine 96 (3.9 M in THF; 1.0 mL, 3.90 mmol, 1.0 equiv.), maintaining

both solutions at –78°C throughout the addition. The reaction mixture was allowed to warm

slowly from –78°C to rt overnight. Aqueous HCl (2 M; 20 mL, 40.0 mmol, ~10 equiv.) was

added and the solution stirred for 1 h. The aqueous layer was extracted with EtOAc (3×50 mL)

and the combined organic layers washed with brine, dried over MgSO4 and filtered.

Concentration under reduced pressure and chromatography (10→25% EtOAc–hexane) yielded

(3R*,4R*,5S*)-methyl 4-((tert-butyldimethylsilyloxy)methyl)-6-(1-methylindol-3-yl)-5-(4-

methylphenylsulfonamido)-3-(phenylsulfonyl)hexanoate (102a) and (3S*,4R*,5S*)-methyl 4-

((tert-butyldimethylsilyloxy)methyl)-6-(1-methylindol-3-yl)-5-(4-methylphenylsulfonamido)-3-

(phenylsulfonyl)hexanoate (102b) as amorphous solids (1.17g, 41%) and the unwanted

regioisomers (3R*,4S*,5R*)-methyl 6-(tert-butyldimethylsilyloxy)-4-((1-methylindol-3-

yl)methyl)-5-(4-methylphenylsulfonamido)-3-(phenylsulfonyl)hexanoate (111a) and

(3S*,4S*,5R*)-methyl 6-(tert-butyldimethylsilyloxy)-4-((1-methylindol-3-yl)methyl)-5-(4-

methylphenylsulfonamido)-3-(phenylsulfonyl)hexanoate (111b) as amorphous solids (~15:10:6:5

102a:111a:111b:102b ratio obtained by 1H NMR analysis of the crude material);

Experimental

143

(3R*,4R*,5S*)-Methyl 4-((tert-butyldimethylsilyloxy)methyl)-6-(1-methylindol-3-yl)-5-(4-

methylphenylsulfonamido)-3-(phenylsulfonyl)hexanoate (102a)

Rf 0.41 (20% EtOAc–hexane). FTIR (film) max: 2928, 2859, 1742, 1156 cm–1

; m/z (CI) 713

[M+H]+ (Found [M+H]


+, 713.2750).

δH (500 MHz, CDCl3) 7.67––7.60 (4H, m, ortho-Ts and ortho-PhSO2), 7.57 (1H, t, J 8.0 Hz,

para-PhSO2), 7.41 (2H, t, J 8.0 Hz, meta-PhSO2), 7.29––7.21 (2H, m, 12 and 9), 7.21 (1H,

t, J 8.0 Hz, 11) 7.16 (2H, d, J 8.0 Hz, meta-Ts), 7.01 (1H, td, J 8.0, 1.0 Hz, 10), 6.83 (1H, s, 2),

5.91 (1H, d, J 9.0 Hz, N4H), 4.23 (1H, dt, J 8.5, 4.0 Hz, 15), 3.79––3.71 (1H, m, 5),

3.71––3.65 (4H, s, OMe then 17a), 3.53 (1H, dd, J 10.5 5.5 Hz, 17b), 3.45 (3H, s, N1Me), 3.10

(1H, dd, J 14.5, 6.5 Hz, 6a), 2.98 (1H, dd, J 18.0, 3.0 Hz, 14a), 2.87 (1H, dd, J 14.5, 6.5 Hz, 6b),

2.76 (1H, dd, J 18.0, 9.0 Hz, 14b), 2.60 (1H, m, 16), 2.39 (3H, s, TsMe), 0.75 (9H, s, Me3CSi),

–0.09 (3H, s, MeSi), –0.13 (3H, s, MeSi);

δC (125 MHz, CDCl3) 171.1 (C3), 142.9 (para-Ts), 138.2 (ipso-PhSO2), 138.0 (ipso-Ts), 136.9

(C13), 133.7 (para-PhSO2), 129.4 (meta-Ts), 129.1 (meta-PhSO2), 128.8 (ortho-PhSO2), 128.2

(C2), 128.1 (C8), 126.8 (ortho-Ts), 121.5 (C11), 119.1 (C10), 118.6 (C12), 109.2 (C9), 108.8

(C7), 62.8 (C17), 61.0 (C15), 52.4 (C5), 51.9 (OMe), 42.9 (C16), 32.6 (N1Me), 30.9 (C14), 29.5

(C6), 25.6 (Me3CSi), 21.5 (TsMe), 17.9 (Me3CSi), –5.8 (MeSi), –5.9 (MeSi).

Experimental

144

(3S*,4R*,5S*)-Methyl 4-((tert-butyldimethylsilyloxy)methyl)-6-(1-methylindol-3-yl)-5-(4-

methylphenylsulfonamido)-3-(phenylsulfonyl)hexanoate (102b)

Rf 0.14 (20% EtOAc–hexane); max (film) 2928, 2858, 1734, 1471, 1447, 1152 cm-1

; m/z (ES)

735 [M+Na]+ (Found [M+Na]

+, 735.2568. C36H48N2O7S2Si requires [M+Na]

+, 735.2570);

δH (400 MHz, CDCl3) 7.86 (2H, app. d, J 8.0 Hz, ortho-PhSO2), 7.54 (1H, t, J 7.5 Hz, para-

PhSO2), 7.45 (2H, t, J 7.5 Hz, meta-PhSO2), 7.39 (2H, app. d, J 8.0 Hz, ortho-Ts), 7.15 (2H, d,

J 3.5 Hz, 12 and 9), 7.04––6.91 (4H, m, 10, 11 and meta-Ts), 6.66 (1H, s, 2), 4.66 (1H, d, J 8.0

Hz, N4H), 4.05 (1H, dt, J 8.0, 2.5 Hz, 15), 4.00 (1H, dd, J 7.0, 3.0 Hz, 5), 3.94 (1H, dd, J 10.0,

3.0 Hz, 17a), 3.85 (1H, dd, J 10.0, 4.0 Hz, 17b), 3.62 (3H, s, N1Me), 3.57 (3H, s, OMe), 3.15

(1H, dd, J 18.0, 3.0 Hz, 14a), 2.86 (1H, dd, J 18.0, 8.5 Hz, 14b), 2.86 (1H, dd, J 14.5, 6.5 Hz,

6a), 2.65––2.56 (2H, m, 6b and 16), 2.31 (3H, s, TsMe), 0.82 (9H, s, Me3CSi), 0.06 (3H, s,

MeSi), 0.00 (3H, s, MeSi);

δC (100 MHz, CDCl3) 171.9 (C3), 143.0 (para-Ts), 137.3 (ipso-PhSO2), 136.9 (C13), 136.3

(ipso-Ts), 133.9 (para-PhSO2), 129.1 (meta- and ortho-PhSO2), 127.5 (C8), 127.4 (C2), 127.0

(ortho- and meta-Ts), 121.6 (C11), 119.0 (C10), 118.5 (C12), 109.1 (C9), 108.8 (C7), 59.8

(C17), 59.3 (C15), 53.0 (C5), 52.4 (OMe), 41.5 (C16), 32.5 (N1Me), 30.2 (C14), 28.9 (C6), 25.8

(Me3CSi), 23.9, 21.6 (TsMe), 18.0 (Me3CSi), –5.5 (MeSi), –5.6 (MeSi).

Experimental

145

(3R*,4S*,5R*)-Methyl 6-(tert-butyldimethylsilyloxy)-4-((1-methylindol-3-yl)methyl)-5-(4-

methylphenylsulfonamido)-3-(phenylsulfonyl)hexanoate (111a)

Rf 0.36 (20% EtOAc–hexane); max (film) 2928, 2859, 1742, 1156 cm-1

; m/z (ES) 713 [M+H]

+

(Found [M+H]+, 713.2750. C36H48N2O7S2Si requires [M+H]

+, 713.2755);

δH (400 MHz, CDCl3) 7.97 (1H, d, J 8.0 Hz, 12), 7.93 (2H, app. d, J 8.0 Hz, ortho-PhSO2),

7.68 (2H, app. d, J 8.0 Hz, ortho-Ts), 7.62 (1H, t, J 8.0 Hz, para-PhSO2), 7.51 (2H, t, J 8.0 Hz,

meta-PhSO2), 7.30––7.20 (4H, m, 9, 11 and meta-Ts), 7.18––7.12 (2H, m, 10 and 2), 5.16 (1H,

d,

J 9.5 Hz, N4H), 4.31 (1H, dd, J 8.0, 2.5 Hz, 15), 3.78 (3H, s, N1Me), 3.61––3.56 (1H, m, 5), 3.48

(3H, s, OMe), 3.29––3.21 (2H, m, 14a and 6a), 3.13 (1H, dd, J 10.5, 2.5 Hz, 17a), 3.01––2.86

(4H, m, 17b, 14b, 16 and 6b), 2.39 (3H, s, TsMe), 0.71 (9H, s, Me3CSi), 0.24 (3H, s, MeSi),

–0.26 (3H, s, MeSi);

δC (100 MHz, CDCl3) 172.0 (C3), 143.6 (para-Ts), 137.8 (ipso-Ts), 137.8 (para-PhSO2), 137.2

(C13), 133.7 (ipso-PhSO2), 129.8 (meta-Ts), 129.1 (ortho-PhSO2), 129.1 (meta-PhSO2), 128.6

(C2), 127.8 (C8), 127.0 (ortho-Ts), 121.5 (C11), 119.9 (C12), 119.1 (C10), 111.7 (C7), 108.9

(C9), 65.0 (C17), 60.0 (C15), 54.0 (C5), 52.2 (OMe), 39.5 (C16), 32.6 (N1Me), 30.3 (C14), 25.7

(Me3CSi), 24.2 (C6), 21.5 (TsMe), 18.2 (Me3CSi), –5.5 (MeSi), –5.6 (MeSi).

Experimental

146

(3S*,4S*,5R*)-Methyl 6-(tert-butyldimethylsilyloxy)-4-((1-methylindol-3-yl)methyl)-5-(4-

methylphenylsulfonamido)-3-(phenylsulfonyl)hexanoate (111b)

Rf 0.23 (20% EtOAc–hexane); max (film) 2955, 2931, 2860, 1734, 1471, 1444, 1157 cm-1

; m/z

(ES) 713 [M+H]+ (Found [M+H]


+, 713.2755);

δH (400 MHz, CDCl3) 7.85 (2H, app. d, J 8.0 Hz, ortho-Ts), 7.40 (2H, app. d, J 8.0 Hz, ortho-

PhSO2), 7.36––7.26 (3H, m, meta-Ts and para-PhSO2), 7.14––7.08 (3H, m, 9, 11 and 12),

6.98––6.88 (3H, m, meta-PhSO2 and 10), 6.72 (1H, s, 2), 6.31 (1H, d, J 9.0 Hz, N4H), 4.25 (1H,

dd, J 8.0, 3.5 Hz, 15), 3.87 (1H, dd, J 10.5, 1.5 Hz, 17a), 3.76––3.70 (1H, m, 17b), 3.63 (2×3H,

s, N1Me and OMe), 3.56––3.48 (1H, m, 5), 3.00––2.88 (2H, m, 14a and 6a), 2.81 (1H, dt, J 10.0,

3.5 Hz, 16), 2.50––2.36 (5H, m, 14b, 6b and 3H, s, TsMe), 0.91 (9H, s, Me3CSi), 0.03 (3H, s,

MeSi), –0.03 (3H, s, MeSi);

δC (100 MHz, CDCl3) 172.1 (C3), 143.4 (para-Ts), 139.1 (ipso-Ts), 137.8 (para-PhSO2), 137.0

(C13), 132.9 (ipso-PhSO2), 129.9 (meta-Ts), 126.6 (C2), 128.0 (ortho-PhSO2), 127.9 (C8),

127.0 (meta-PhSO2), 126.9 (ortho-Ts), 121.5 (C11), 118.8 (C12), 118.7 (C10), 110.3 (C7),

109.2 (C9), 63.1 (C17), 61.3 (C15), 55.8 (C5), 52.3 (OMe), 38.6 (C16), 32.5 (N1Me), 29.3

(C14), 26.4 (C6), 26.0 (Me3CSi), 21.5 (TsMe), 18.3 (Me3CSi), –5.50 (Me2Si).

Experimental

147

(4R*,5S*,E)-Methyl 4-(hydroxymethyl)-6-(1-methylindol-3-yl)-5-(4-

methylphenylsulfonamido)hex-2-enoate (114)

To a solution of OTBS-amino alcohol 102 (58.3 mg, 0.081 mmol, 1.0 equiv.) in THF (3 mL) at

0°C was added TBAF·3H2O (28.4 mg, 0.090 mmol, 1.1 equiv.) and the reaction mixture allowed

to stir for 15 min. Saturated aqueous NH4Cl (2 mL) was added and the aqueous layer extracted

with EtOAc (3×10 mL). The organic layers were combined, dried over MgSO4 and filtered.

Concentration under reduced pressure and flash column chromatography (50% EtOAc–hexane)

yielded (4R*,5S*,E)-methyl 4-(hydroxymethyl)-6-(1-methylindol-3-yl)-5-(4-

methylphenylsulfonamido)hex-2-enoate 114 (36.9 mg, 76%) as a pale yellow gum;

Rf 0.32 (50% EtOAc–hexane); max (film) 3508, 3364, 2933, 1810, 1783, 1598, 1325, 1184,

1091, 739 cm-1

; m/z (CI) 457 [M+H]+ (Found [M+H]

+, 457.1790. C24H28N2O5S requires

[M+H]+, 457.1751);

δH (400 MHz, CDCl3) 7.45 (2H, app. d, J 8.0 Hz, ortho-Ts), 7.20––7.10 (3H, m, 9, 12 and 11),

7.04––6.97 (3H, m, meta-Ts and 10), 6.91 (1H, dd, J 16.0, 9.0 Hz, 15), 6.63 (1H, s, 2), 5.99 (1H,

d, J 16.0 Hz, 14), 5.02 (1H, d, J 9.0 Hz, N4HTs), 4.00––3.89 (2H, m, 17a and 17b), 3.77 (3H, s,

N1Me), 3.59 (3H, s, OMe), 3.03 (1H, dd, J 8.0, 6.0 Hz, 5), 2.80––2.69 (2H, m, 6a and 16), 2.61

(1H, dd, J 14.5 Hz, 6b), 2.34 (3H, s, TsMe);

δC (100 MHz, CDCl3) 166.6 (C3), 144.1 (C15), 143.0 (para-Ts), 136.9 (ipso-Ts and C13), 129.8

(ortho-Ts), 129.1 (meta-Ts), 127.4 (C8), 127.3 (C2), 126.6 (C9), 125.3 (C14), 121.6 (C11),

119.0 (C10), 118.4 (C12), 109.2 (C7), 61.9 (C17), 53.3 (C5), 51.8 (OMe), 48.1 (C16), 32.5

(N1Me), 29.7 (C6), 21.6 (TsMe).

Experimental

148

(3R*,4R*,5S*)-Methyl 4-(hydroxymethyl)-6-(1-methylindol-3-yl)-5-(4-

methylphenylsulfonamido)-3-(phenylsulfonyl)hexanoate (89)

To a solution of OTBS-amino alcohol 102 (23.0 mg, 0.032 mmol, 1.0 equiv.) in MeOH (3 mL)

at rt was added concentrated HCl (1 drop) and the solution stirred for 16 h. The reaction mixture

was then cooled to –78°C and NH3 (~0.1 M in MeOH; 0.50 mL, 0.05 mmol, ~1.5 equiv.) and the

solution stirred for 15 minutes. Concentration under reduced pressure and flash column

chromatography (33% EtOAc–hexane) yielded (3R*,4R*,5S*)-methyl 4-(hydroxymethyl)-6-(1-

methylindol-3-yl)-5-(4-methylphenylsulfonamido)-3-(phenylsulfonyl)hexanoate 89 (18.7 mg,

98%) as a pale yellow oil; Rf 0.32 (50% EtOAc–hexane). Data is in accordance with that

previously reported (Page 138).

(3R*,4R*,5S*)-Methyl 6-(1-methylindol-3-yl)-5-(4-methylphenylsulfonamido)-4-((3-

oxobutanoyloxy)methyl)-3-(phenylsulfonyl)hexanoate (112)

To a solution of amino alcohol 89 (250 mg, 0.418 mmol, 1.0 equiv.) in toluene (1 mL) at rt was

added 2,2,6-trimethyl-4H-1,3-dioxin-4-one (0.11 mL, 0.884 mmol, 2.0 equiv.) and the reaction

mixture heated under reflux at 110°C for 2 h. Saturated aqueous NH4Cl (1 mL) was added and

Experimental

149

the aqueous layer extracted with EtOAc (3×20 mL). The organic phases were combined, dried

over MgSO4 and filtered. Concentration under reduced pressure and chromatography (20%

EtOAc–hexane) yielded (3R*,4R*,5S*)-methyl 6-(1-methylindol-3-yl)-5-(4-

methylphenylsulfonamido)-4-((3-oxobutanoyloxy)methyl)-3-(phenylsulfonyl)hexanoate 112

(151.7 mg, 58%) as an amorphous solid; Rf 0.55 (66% EtOAc–hexane);Rf 0.24 (50% EtOAc–

hexane);max (film) 2925, 1734, 1275, 1156 cm–1

; m/z (CI) 683 [M+H]+ (Found [M+H]

+,

683.2041. C34H38N2O9S2 requires [M+H]+, 683.2019);

δH (400 MHz, CDCl3) 7.86 (2H, app. d, J 8.0 Hz, ortho-Ts), 7.71––7.59 (5H, m, ArH),

7.25––7.10 (3H, m, ArH), 7.06––6.95 (3H, m, ArH), 6.90 (1H, s, 2), 5.70 (1H, d, J 9.0 Hz,

N4H), 4.40 (1H, dd, J 11.5, 6.5 Hz, 15), 4.22 (1H, dt, J 6.0, 3.0 Hz, 17a), 4.05––3.83 (3H, m, 5

and 17b), 3.68 (3H, s, N1Me), 3.38 (3H, s, OMe), 3.21––3.11 (2H, m, 14a and 14b),

2.93––2.81 (2H, m, 6a and 6b), 2.54––2.46 (1H, m, 16), 2.38 (3H, s, TsMe), 2.14 (3H, s, 18),

2.04 (2H, s, 20);

δC (100 MHz, CDCl3); 205.3 (19), 170.7 (21), 166.6 (C3), 142.9 (para-Ts), 137.8 (ipso-PhSO2),

137.6 (ipso-Ts), 136.9 (C13), 134.2 (para-PhSO2), 129.6 (C8), 129.3 (meta-Ts), 129.2 (meta-

PhSO2), 129.0 (ortho-PhSO2), 128.8 (ortho-Ts), 127.7 (C2), 121.7 (C11), 119.1 (C10), 118.5

(C12), 109.0 (C9), 107.5 (C7), 60.1 (C17), 59.2 (OMe), 53.2 (C15), 52.2 (C5), 46.8 (C16) 37.2

(C14), 35.9 (C18), 34.1 (C20), 32.5 (N1Me), 29.0 (C6), 21.6 (TsMe).

Microwave Prep. For (112)

To a solution of amino alcohol 89 (15.0 mg, 0.025 mmol, 1.0 equiv.) in toluene (1 mL) in a

microwave vial was added 2,2,6-trimethyl-4H-1,3-dioxin-4-one (0.005 mL, 0.038 mmol, 1.5

equiv.) and the reaction mixture heated in the microwave at 150°C for 30 min. Saturated aqueous

NH4Cl (1 mL) was added and the aqueous layer extracted with EtOAc (3×5 mL) and CH2Cl2

(3×5 mL). The organic phases were combined, dried over MgSO4 and filtered. Concentration

under reduced pressure and chromatography (20% EtOAc–hexane) yielded (3R*,4R*,5S*)-

methyl 6-(1-methylindol-3-yl)-5-(4-methylphenylsulfonamido)-4-((3-oxobutanoyloxy)methyl)-3-

(phenylsulfonyl)hexanoate 112 (14.1 mg, 76%) as an amorphous solid.

Experimental

150

((2S*,3R*)-2-((1-Methylindol-3-yl)methyl)-6-oxo-1-tosyl-1,2,3,6-tetrahydropyridin-3-

yl)methyl 3-oxobutanoate (113)

To 112 (31.0 mg, 0.045 mmol, 1.0 equiv.) in toluene (1 mL) was added trimethylaluminium (2.0

M in hexanes; 0.025 mL, 0.05 mmol, 1.1 equiv.) and the reaction heated under reflux at 100°C

for 1 hour. The reaction mixture was then cooled to rt and saturated aqueous NH4Cl (5 mL) was

added. The aqueous layer was extracted with EtOAc (3×20 mL) and CH2Cl2 (3×20 mL). The

organic layers were combined, washed with brine, dried over MgSO4 and filtered. Concentration

under reduced pressure and chromatography (33% EtOAc–hexane) yielded (5R*,6S*)-5-

(hydroxymethyl)-6-((1-methylindol-3-yl)methyl)-1-tosyl-5,6-dihydropyridin-2(1H)-one 90 as an

amorphous solid (14.1 mg, 61%); Data is in accordance with that reported later (Page 154).

3.1.5 Procedures from final synthesis of key intermediate lactam–alcohol 90 (Sections 2.1.14)

4-Methyl-N-((S*)-2-(1-methyl-1H-indol-3-yl)-1-((3R*,4R*)-6-oxo-4-

(phenylsulfonyl)tetrahydro-2H-pyran-3-yl)ethyl)benzenesulfonamide (109a) and 4-methyl-

N-((S*)-2-(1-methyl-1H-indol-3-yl)-1-((3R*,4S*)-6-oxo-4-(phenylsulfonyl)tetrahydro-2H-

pyran-3-yl)ethyl)benzenesulfonamide (109b)

Experimental

151

To a solution of trimethyl 3-(phenylsulfonyl)orthopropionate 88 (7.43g, 27.08 mmol, 1.5 equiv.)

in THF (30 mL) at –78 °C was added n-BuLi (2.48 M in hexanes; 12.0 mL, 29.80 mmol, 1.7

equiv.) and the solution stirred for 1 h at –78°C.

Meanwhile, n-BuLi (2.48 M in hexanes; 8.0 mL, 19.9 mmol, 1.1 equiv.) was added to a solution

of hydroxymethyl aziridine 82 (6.69 g, 18.05 mmol, 1.0 equiv.) in THF (10.0 mL) at

–78°C and the solution stirred for 1 h at –78°C.

The dark red solution of deprotonated 88 was added dropwise via cannula to the dark green

solution of O-lithio hydroxymethyl aziridine 82, maintaining both solutions at –78°C throughout

the addition. The reaction mixture was allowed to warm slowly from –78°C to rt overnight.

Aqueous HCl (2 M; 50 mL, 100.0 mmol, 100 equiv.) was added and the solution stirred for 3 h.

The aqueous layer was extracted with EtOAc (3×200 mL) and CH2Cl2 (3×100 mL), and the

combined organic layers washed with brine, dried over MgSO4 and filtered. Concentration under

reduced pressure and chromatography (50% EtOAc–hexane) yielded lactones 109 (8.18 g, 80%)

as a 2:1 mixture of sulfone epimers.

4-Methyl-N-((S*)-2-(1-methylindol-3-yl)-1-((3R*,4R*)-6-oxo-4-(phenylsulfonyl)tetrahydro-

2H-pyran-3-yl)ethyl)benzenesulfonamide (109a)

Rf 0.25 (50% EtOAc–hexane); 225.9–226.6°C; FTIR (film) max: 3297, 2921, 1739, 1599 cm–1

;



+, 567.1624);

(Found C, 61.38; H, 5.40; N, 5.05%. C29H30N2O6S2 requires C, 61.46; H, 5.34; N, 4.94%);

δH (400 MHz, CDCl3) 8.00 (2H, dd, J 8.0, 1.0 Hz, meta-PhSO2), 7.84 (2H, dd, J 8.0, 1.0 Hz,

ortho-PhSO2), 7.66 (1H, tt, J 7.5, 1.0 Hz, para-PhSO2), 7.45 (2H, d, J 8.0 Hz, ortho-Ts),

7.24––7.22 (2H, m, 9 and 11), 7.11––7.01 (4H, m, meta-Ts, 12 and 10), 6.72 (1H, s, 2),

4.70 (1H, d, J 7.5 Hz, N4H), 4.49 (1H, dd, J 12.5, 4.0 Hz, 17a), 4.31 (1H, dd, J 12.5, 4.0 Hz,

Experimental

152

17b), 3.81––3.76 (1H, m, 15), 3.69 (3H, s, N1Me), 3.66––3.60 (1H, m, 5), 2.97 (1H, dd, J 15.0,

5.0 Hz, 6a), 2.82––2.74 (2H, m, 6b and 14a), 2.61 (1H, dd, J 16.0, 7.0 Hz, 14b), 2.36 (3H, s,

TsMe);

δC (100 MHz, CDCl3) 168.7 (C3), 143.5 (para-Ts), 137.0 (C13), 136.2 (ipso-PhSO2),

135.6 (ipso-Ts), 134.5 (para-PhSO2), 129.6 (ortho-PhSO2), 129.5 (meta-Ts),

129.1 (meta-PhSO2), 127.8 (C8), 127.4 (C2), 126.7 (ortho-Ts), 122.1 (C11), 119.6 (C10),

118.2 (C12), 109.5 (C9), 107.2 (C7), 66.5 (C17), 56.8 (C15), 53.7 (C5), 36.6 (C16), 32.7

(N1Me), 29.0 (C14), 28.1 (C6), 21.6 (TsMe).

4-Methyl-N-((S*)-2-(1-methylindol-3-yl)-1-((3R*,4S*)-6-oxo-4-(phenylsulfonyl)tetrahydro-

2H-pyran-3-yl)ethyl)benzenesulfonamide (109b)

Rf 0.15 (50% EtOAc–hexane); 214.5–215.0°C FTIR (film) max: 3297, 2921, 1739, 1599 cm–1

;



+, 567.1624).

(Found C, 61.38; H, 5.40; N, 5.05%. C29H30N2O6S2 requires C, 61.46; H, 5.34; N, 4.94%);

δH (400 MHz, CDCl3) 8.03––7.98 (2H, m, ortho-PhSO2), 7.71 (1H, tt, J 7.5, 1.0 Hz,

para-PhSO2), 7.61 (2H, t, J 8.0 Hz, meta-PhSO2), 7.42––7.35 (3H, m, ortho-Ts and 12), 7.17

(2H, d, J 4.0 Hz, 9 and 11), 7.01––6.95 (1H, m, 10), 6.92 (2H, J 8.0 Hz, meta-Ts), 6.71 (1H, s,

2), 5.35 (1H, d, J 6.5 Hz, N4H), 5.03 (1H, dd, J 12.0, 8.0 Hz, 17a), 4.43––4.21 (2H, m, 17b and

5), 4.03––3.96 (1H, m, 15), 3.63 (3H, s, N1Me), 3.18––3.02 (2H, m, 6a and 16), 2.92––2.74 (2H,

m, 6b and 14a), 2.51 (1H, dd, J 18.0, 7.0 Hz, 14b), 2.29 (3H, s, TsMe);

δC (100 MHz, CDCl3) 166.9 (C3), 143.2 (para-Ts), 137.7 (para-PhSO2), 137.0 (C13),

135.8 (ipso-Ts), 134.7 (ipso-PhSO2), 129.8 (ortho-PhSO2), 129.2 (meta-Ts), 128.8 (meta-

PhSO2), 127.4 (C8), 127.2 (C2), 126.7 (ortho-Ts), 121.9 (C11), 119.4 (C10), 118.6 (C12),

Experimental

153

109.3 (C9), 108.3 (C7), 68.8 (C17), 57.3 (C15), 52.7 (C5), 38.9 (C16), 32.6 (N1Me), 31.6

(C14), 28.1(C6), 21.6 (TsMe).

(4S*,5R*,6S*)-5-(hydroxymethyl)-6-((1-methylindol-3-yl)methyl)-4-(phenylsulfonyl)-1-

tosylpiperidin-2-one (118)

To a stirred solution of 4-Methyl-N-((S*)-2-(1-methylindol-3-yl)-1-((3R*,4R*)-6-oxo-4-

(phenylsulfonyl)tetrahydro-2H-pyran-3-yl)ethyl)benzenesulfonamide 109a (1.5 g, 2.65 mmol, 1.0

equiv.) in toluene (9 mL) at 0°C was added trimethyl aluminium (2.0 M in hexanes; 1.6 mL, 3.18

mmol, 1.2 equiv.) and the reaction mixture stirred at 0°C for 1 h. Saturated aqueous NH4Cl (10

mL) was added and the aqueous layer extracted with EtOAc (3×50 mL) and CH2Cl2 (3×50 mL).

The organic layers were combined, washed with brine, dried over MgSO4 and filtered.


(4S*,5R*,6S*)-5-(hydroxymethyl)-6-((1-methylindol-3-yl)methyl)-4-(phenylsulfonyl)-1-

tosylpiperidin-2-one 118 as a crystalline white solid (0.99 g, 30%) and (5R*,6S*)-5-

(hydroxymethyl)-6-((1-methylindol-3-yl)methyl)-1-tosyl-5,6-dihydropyridin-2(1H)-one 90 as an

amorphous solid (1.49 g, 69%); 266.0–269.0°C; Rf 0.75 (66% EtOAc–hexane); FTIR (film) max:

3529, 2925, 1704, 1162 cm–1

; m/z (ES) 567 [M+H]+ (Found [M+H]

+, 567.1711. C29H30N2O6S2

requires [M+H]+, 567.1739). Found C, 61.53; H, 5.27; N, 4.92%. C23H24N2O4S requires C,

61.46; H, 5.34; N, 4.94%;

δH (400 MHz, CDCl3) 8.02––7.89 (3H, m, ortho-PhSO4 and para-PhSO4), 7.89––7.79 (2H, m,

ortho-Ts), 7.69 (1H, tt, J 8.0, 1.0 Hz, 10), 7.57 (2H, t, J 8.0 Hz, meta-PhSO4), 7.34 (1H, d, J 8.0

Hz, 11), 7.31––7.15 (4H, m, meta-Ts, 9 and 12), 5.10 (1H, t, J 8.0 Hz, 5), 3.80 (3H, s, N1Me),

3.48––3.36 (2H, m, 17a and 15), 3.35––3.17 (3H, m, 6a, 6b and 17b), 3.10 (1H, dd, J 15.5, 13.0

Experimental

154

Hz, 14a), 2.98 (1H, td, J 7.0, 4.5 Hz, 16), 2.41 (3H, s, TsMe), 2.36 (1H, dd, J 15.5, 7.0 Hz, 14b),

1.76 (1H, dd, J 7.0, 5.0 Hz, OH);

δC (100 MHz, CDCl3) 166.8 (C3), 145.3 (para-Ts) , 137.3 (para-PhSO2), 136.8 (C13), 135.4

(ipso-Ts), 134.6 (ipso-PhSO2), 129.7 (ortho-PhSO2), 129.3 (C2 and meta-Ts), 129.2 (ortho-Ts),

128.6 (meta-PhSO2), 127.5 (C8) 121.9 (C11), 119.5 (C10), 119.3 (C12), 109.4 (C9), 108.7

(C7), 64.9 (C17), 58.1 (C15), 57.5 (C5), 35.5 (C16), 33.2 (C14), 32.8 (N1Me), 32.1 (C6), 21.7

(TsMe).

(5R*,6S*)-5-(Hydroxymethyl)-6-((1-methylindol-3-yl)methyl)-1-tosyl-5,6-dihydropyridin-

2(1H)-one (90)

To a solution of lactones 109 (7.76 g, 13.71 mmol, 1.0 equiv.) in toluene (50 mL) was added

trimethylaluminium (2.0 M in hexanes; 10.5 mL, 21.0 mmol, 1.5 equiv.) and the reaction

mixture heated under reflux at 120°C for 2 h. The reaction mixture was cooled to rt before

saturated aqueous Rochelle salt (10 mL) and EtOAc (10 mL) were added, and the resulting

suspension was stirred vigorously at rt overnight. Saturated aqueous NaHCO3 (1 mL) was added

and the aqueous layer extracted with EtOAc (3×100 mL) and CH2Cl2 (3×100 mL). The organic

layers were washed with brine, dried over MgSO4 and filtered. Concentration under reduced

pressure and chromatography (33% EtOAc–hexane) yielded (5R*,6S*)-5-(hydroxymethyl)-6-((1-

methylindol-3-yl)methyl)-1-tosyl-5,6-dihydropyridin-2(1H)-one 90 as a colourless, amorphous

solid (5.66 g, 94%); Rf 0.25 (66% EtOAc–hexane); FTIR (film) max: 3530, 3056, 2917, 1687

cm–1

; m/z (CI) 425 [M+H]+ (Found [M+H]


+,

425.1535). Found C, 64.94; H, 5.63; N, 6.57%. C23H24N2O4S requires C, 65.07; H, 5.70; N,

6.60%;

Experimental

155

δH (400 MHz, CDCl3) 7.99 (2H, d, J 8.0 Hz, meta-Ts), 7.68 (1 H, d, J 8.0 Hz, 12), 7.33––7.21

(4H, m, ortho-Ts, 9 and 11), 7.15 (1H, t, J 8.0 Hz, 10), 6.90 (1H, s, 2), 6.57 (1H, ddd, J 10, 8.0,

1.5 Hz, 15), 5.94 (1H, d, J 10.0 Hz, 14), 5.16 (1H, dd, J 11.0, 4.0 Hz, 5), 3.75 (3H, s, N1Me),

3.57 (1H, dd, J 11.0, 6.0 Hz, 17a), 3.38 (1H, t, J 9.0 Hz, 17b), 3.31 (1H, dd, J 14.0, 4.0 Hz, 6a),

3.14 (1H, dd, J 14.0, 11.0 Hz, 6b), 2.69 (1H, dt, J 7.5, 6.0 Hz, 16), 2.42 (3H, s, TsMe), 1.59 (1H,

br. s, OH);

δC (100 MHz, CDCl3) 161.6 (C3), 144.7 (para-Ts), 142.4 (C15), 137.0 (C13), 136.4 (ipso-Ts),

129.3 (meta-Ts), 129.1 (ortho-Ts), 127.94 (C2), 127.85 (C8), 125.9 (C14), 121.9 (C11), 119.4

(C10), 118.9 (C12), 109.5 (C7), 109.4 (C9), 62.9 (C17), 57.0 (C5), 39.9 (C16), 32.7 (N1Me),

29.9 (C6), 21.7 (TsMe).

Experimental procedure for O- → N-transacylation of sulfone (110)

To a solution of crude lactone 110 (366.2 mg, 0.863 mmol, 1.0 equiv.) in toluene (2 mL) was

added trimethylaluminium (2.0 M in hexanes; 0.5 mL, 0.95 mmol, 1.1 equiv.) and the reaction

mixture stirred at rt for 1 h. The reaction mixture was then heated to 100°C for 15 min in the

microwave, cooled to rt and saturated aqueous NH4Cl (5 mL) was added. The aqueous layer was

extracted with EtOAc (3×20 mL) and CH2Cl2 (3×20 mL). The organic layers were combined,

washed with brine, dried over MgSO4 and filtered. Concentration under reduced pressure and

chromatography (33% EtOAc–hexane) yielded (5R*,6S*)-5-(hydroxymethyl)-6-((1-methylindol-

3-yl)methyl)-1-tosyl-5,6-dihydropyridin-2(1H)-one 90 as an amorphous solid (334 mg, 91%);

Data is in accordance with that previously reported (Page 154).

Experimental

156

3.1.6 Procedures from synthesis of pentacyclic lactone 85 (Sections 2.2.1 and 2.2.2)


yl)methyl 3-oxobutanoate (113) – Small Scale Original Prep.

To a stirred solution of lactam alcohol 90 (10.9 mg, 0.026 mmol, 1.0 equiv.) and KOAc (0.25

mg, 0.003 mmol, 0.1 equiv.) in THF (0.15 mL) at rt was added diketene (0.66M in THF; 0.05

mL, 0.033 mmol, 1.3 equiv.) and the reaction mixture heated under reflux at 70°C for 1.25 h.

After cooling to rt, water (0.5 mL) was added and the aqueous layer extracted with EtOAc (3×10

mL). The organic layers were combined, washed with brine, dried over MgSO4 and filtered.

Concentration under reduced pressure chromatography (40% EtOAc–hexane) yielded

((2S*,3R*)-2-((1-methylindol-3-yl)methyl)-6-oxo-1-tosyl-1,2,3,6-tetrahydropyridin-3-yl)methyl

3-oxobutanoate 113 (17.1 mg, 100%) as an amorphous solid; For data, please refer to optimised

route (Page 162).

Experimental

157

(4aR*,6R*,8S*,8aR*,Z)-6-Hydroxy-4-(1-hydroxyethylidene)-8-((1-methylindol-3-

yl)methyl)-7-tosylhexahydro-1H-pyrano[3,4-c]pyridin-3(4H)-one (119)

To a solution of enol 91 (54.7 mg, 0.108 mmol, 1.0 equiv.) in THF (1 mL) at –78°C was added

DIBAL (1.0 M in toluene; 0.22 mL, 0.215 mmol, 2.0 equiv.) and the solution stirred at –78°C for

3 h. MeOH (1 mL) was added and the reaction mixture was allowed to warm slowly from –78°C

to rt. Saturated aqueous Rochelle salt (5 mL) and EtOAc (15 mL) were added and the resulting

suspension stirred vigorously at rt overnight. The aqueous phase was extracted with EtOAc

(3×50 mL) and the organic phases were combined, dried over MgSO4 and filtered. Concentration

under reduced pressure and preparative thin layer chromatography (50% EtOAc–hexane) yielded

(4aR*,6R*,8S*,8aR*,Z)-6-hydroxy-4-(1-hydroxyethylidene)-8-((1-methylindol-3-yl)methyl)-7-

tosylhexahydro-1H-pyrano[3,4-c]pyridin-3(4H)-one 119 (28.0 mg, 51%) as a white amorphous

solid; Rf 0.61 (50% EtOAc–hexane); FTIR (film) max: 3481, 2925, 1631, 1614, 1477, 1439 cm–

1; m/z (ES) 509 [M–H]

– (Found [M–H]

–, 509.1754. C27H30N2O6S requires [M–H]

–, 509.1746);

δH (400 MHz, CDCl3) 13.85 (1H, s, 19-OH), 7.69 (2H, app. d, J 8.0 Hz, ortho-Ts), 7.37––7.23

(3H, m, 9, 11 and 12), 7.17 (1H, t, J 8.0 Hz, 10), 6.89 (1H, s, 2), 5.53 (1H, br. s, 3), 3.96 (1H, dd,

J 12.0, 3.0, Hz, 5), 3.77 (3H, s, N1Me), 3.69––3.55 (3H, m, 17a, 17b and 6a) 3.51––3.38 (2H, m,

6b and 15), 3.17 (1H, s, 3-OH), 2.46 (3H, s, TsMe), 2.37––2.28 (1H, m, 16) 2.20 (3H, s, 18),

1.91 (1H, dd, J 14.0, 4.5 Hz, 14a), 1.49 (1H, td, J 14.0, 3.5 Hz, 14b);

δC (100 MHz, CDCl3) 176.8 (C19), 171.8 (C21), 144.2 (para-Ts), 137.3 (C13), 137.2 (ipso-Ts),

130.1 (meta-Ts), 129.2 (C8), 127.5 (C2), 126.6 (ortho-Ts), 122.0 (C11), 119.4 (C10), 119.2

Experimental

158

(C12), 111.2 (C9), 109.4 (C7), 96.6 (C20), 67.1 (C17), 54.3 (C5), 32.7 (N1Me), 32.5 (C6), 31.3

(C16), 22.1 (C15), 21.6 (TsMe), 18.2 (C18).

Pentacyclic lactone (85)

To a solution of aminol 119 (20 mg, 0.049 mmol, 1.0 equiv.) in THF (1 mL) at –78°C was added

TFA (1 drop) and the solution stirred at –78°C for 2 h. Saturated aqueous NaHCO3 (2 mL) was

added, and the aqueous phase extracted with EtOAc (3×5 mL) and CH2Cl2 (2×5 mL). The

organic phases were washed with brine, combined, dried over MgSO4, and filtered.


pentacyclic lactone 85 (21.9 mg, 91%) as an amorphous solid; Rf 0.60 (66% EtOAc–hexane);

FTIR (film) max: 3049, 2924, 2854, 1634, 1610, 1468 cm–1

; m/z (CI) 493 [M+H]+ (Found

[M+H]+, 493.1779. C27H28N2O5S requires [M+H]

+, 493.1797);

δH (400 MHz, CDCl3) 14.04 (1H, s, 19-OH), 7.36 (2H, app. d, J 8.0 Hz, ortho-Ts),

7.28––7.15 (3H, m, 9, 11 and 12), 7.04 (1H, t, J 7.0 Hz, 10), 6.81 (2H, app. d, J 8.0 Hz,

meta-Ts), 5.30 (1H, br. s, 3), 4.70 (1H, t, J 12.0 Hz, 17a), 4.41 (1H, ddd, J 12.0, 4.5, 1.0 Hz,

17b), 4.32 (1H, br. d, J 7.5, 5), 3.68 (3H, s, N1Me), 2.94 (1H, dd, J 16.5, 8.0 Hz, 6a),

2.75 (1H, dt, J 12.5 2.5 Hz, 15), 2.50 (1H, d, J 16.5 Hz, 6b), 2.26––2.15 (2H, m, 14a and 16),

2.03 (3H, s, TsMe), 1.74 (1H, ddd, J 14.0, 4.5, 3.0 Hz, 14b), 1.65 (3H, s, 18);

δC (100 MHz, CDCl3) 176.8 (C19), 172.0 (C21), 143.7 (para-Ts), 136.9 (C13),

135.9 (ipso-Ts), 131.4 (C2), 128.9 (meta-Ts), 126.4 (ortho-Ts), 126.0 (C8) 121.9 (C11), 119.4

(C10), 118.0 (C12), 109.0 (C9), 107.2 (C7), 95.7 (C20), 67.5 (C17), 49.3 (C3), 48.1 (C5), 39.7

Experimental

159

(C16), 32.7 (C14), 29.3 (N1Me), 26.1 (C15), 25.3 (C6), 21.1 (TsMe), 18.1 (C18). Data is in

accordance with that previously reported.57

(4aR*,8R*,8aR*,Z)-8-(Ethoxymethyl)-4-(1-hydroxyethylidene)-7-tosyl-4,4a,8,8a-tetrahydro-

1H-pyrano[3,4-c]pyridin-3(7H)-one (120) and (4aR*,8S*,8aR*,Z)-4-(1-Hydroxyethylidene)-

8-((1-methylindol-3-yl)methyl)-7-tosyl-4,4a,8,8a-tetrahydro-1H-pyrano[3,4-c]pyridin-

3(7H)-one (84c)

To a solution of lactam–lactone 91 (50.0 mg, 0.098 mmol, 1.0 equiv.) in THF (5 mL) at

–78°C was added DIBAL (1.0 M in toluene; 0.12 mL, 0.12 mmol, 1.2 equiv.) and the solution

stirred at –78°C for 2 h. The reaction mixture was quenched with wet EtOAc (1 mL) before

trifluoroacetic acid (0.08 mL, 0.10 mmol, 1.0 equiv.) was added and the reaction mixture was

allowed to warm slowly from –78 °C to rt over 30 min. EtOAc (30 mL) and saturated aqueous

Rochelle salt (10 mL) were added, and the resulting suspension stirred vigorously at rt overnight.

Saturated aqueous NaHCO3 (10 mL) was added, and the aqueous phase extracted with EtOAc

(3×50 mL) and CH2Cl2 (2×50 mL). The organic phases were washed with brine, combined, dried

over MgSO4, and filtered. Concentration under reduced pressure and chromatography (33%

EtOAc–hexane) gave (4aR*,6R*,8S*,8aR*,Z)-6-Hydroxy-4-(1-hydroxyethylidene)-8-((1-

methylindol-3-yl)methyl)-7-tosylhexahydro-1H-pyrano[3,4-c]pyridin-3(4H)-one 119 (16.3 mg,

Experimental

160

33%), (4aR*,8S*,8aR*,Z)-4-(1-Hydroxyethylidene)-8-((1-methylindol-3-yl)methyl)-7-tosyl-

4,4a,8,8a-tetrahydro-1H-pyrano[3,4-c]pyridin-3(7H)-one 84c (8.86 mg, 19%), pentacyclic

lactone 85 (8.40 mg, 17%) and (4aR*,8R*,8aR*,Z)-8-(Ethoxymethyl)-4-(1-hydroxyethylidene)-7-

tosyl-4,4a,8,8a-tetrahydro-1H-pyrano[3,4-c]pyridin-3(7H)-one 120 (4.48 mg, 11%).

(4aR*,8R*,8aR*,Z)-8-(Ethoxymethyl)-4-(1-hydroxyethylidene)-7-tosyl-4,4a,8,8a-tetrahydro-

1H-pyrano[3,4-c]pyridin-3(7H)-one (120)

Rf 0.50 (50% EtOAc–hexane). FTIR (film) max: 3055, 1693, 1598, 1448, cm–1

; m/z (CI) 408

[M+H]+ (Found [M+H]

+, 408.1465. C20H25NO6S requires [M+H]

+, 408.1797);

δH (400 MHz, CDCl3) 14.01 (1H, s, 19-OH), 7.67 (2H, app. d, J 8.0 Hz, ortho-Ts),

7.34 (2H, app. d, J 8.0 Hz, meta-Ts), 6.81 (1H, dd, J 8.5, 1.5 Hz, 3), 4.62 (1H, dt, J 8.5, 1.5 Hz,

14), 3.86 (1H, ddd, J 10.0, 5.0, 1.5 Hz, 5), 3.68 (1H, dd, J 10.0, 5.0 Hz, 22a), 3.71––3.44 (3H, m,

6a, 6b and 22b), 3.30––3.21 (2H, m, 15 and 17a), 3.12 (1H, t, J 12.0 Hz, 17b), 2.56––2.48 (1H,

m, 16), 2.45 (3H, s, TsMe), 2.10 (3H, s, 18), 1.19 (3H, t, J 7.0 Hz, 23);

δC (100 MHz, CDCl3) 178.2 (C19), 172.2 (C21), 144.8 (para-Ts), 135.6 (ipso-Ts), 130.2

(meta-Ts), 126.8 (ortho-Ts), 122.5 (C3), 106.5 (C14), 95.2 (C20), 69.4 (C22), 66.9 (C6), 66.4

(C17), 52.3 (C5), 28.6 (C16), 26.6 (C15), 21.7 (TsMe), 18.7 (C18), 15.1 (C23).

Experimental

161

(4aR*,8S*,8aR*,Z)-4-(1-Hydroxyethylidene)-8-((1-methylindol-3-yl)methyl)-7-tosyl-

4,4a,8,8a-tetrahydro-1H-pyrano[3,4-c]pyridin-3(7H)-one (84c)

Rf 0.40 (50% EtOAc–hexane); FTIR (film) max: 3055, 2931, 1691, 1598, 1447, cm–1

; m/z (ES)

493 [M+H]+ (Found [M+H]


+, 493.1797);

δH (400 MHz, CDCl3) 14.02 (1H, s, 19-OH), 7.84 (1H, d, J 8.0 Hz, 9), 7.72 (2H, app. d, J 8.0

Hz, ortho-Ts), 7.37––7.20 (5H, m, 10, 11, 12 and meta-Ts), 6.88 (1H, s, 2), 6.77 (1H, dd, J 8.5,

1.5 Hz, 14), 4.69 (1H, dt, J 8.5, 1.5 Hz, 3), 4.01 (1H, br. d, J 10.5 Hz, 5), 3.77 (3H, s, N1Me),

3.45––3.37 (2H, m, 6a and 15), 3.17––2.97 (3H, m, 6b, 17a and 17b), 2.42 (3H, s, TsMe), 2.16

(3H, s, 18);


130.2 (meta-Ts), 127.6 (C2), 126.7 (ortho-Ts), 122.5 (C3), 122.1 (C11), 119.5 (C10), 119.0

(C9), 109.6 (C12), 109.1 (C7), 105.9 (C14), 95.4 (C20), 66.7 (C17), 53.9 (C5), 32.8 (N1Me),

29.8 (C6), 29.4 (C16), 26.4 (C15), 21.7 (TsMe), 18.8 (C18).

Experimental

162


yl)methyl 3-oxobutanoate (113)

A solution of alcohol 90 (3.53 g, 8.33 mmol, 1.0 equiv.) and 4H-2,2,6-trimethyl-1,3-dioxin-4-

one 115 (1.66 mL, 12.49 mmol, 1.5 equiv.) in toluene (15 mL) was heated to 150°C in the

microwave for 20 min in a sealed tube. On cooling to rt, saturated aqueous NH4Cl (10 mL) was

added and the aqueous layer extracted with EtOAc (3×50 mL) and CH2Cl2 (3×50 mL). The

organic layers were washed with brine, combined, dried over MgSO4 and filtered. Concentration

under reduced pressure and chromatography (20→50% EtOAc–hexane) yielded ((2S*,3R*)-2-

((1-methylindol-3-yl)methyl)-6-oxo-1-tosyl-1,2,3,6-tetrahydropyridin-3-yl)methyl 3-

oxobutanoate 113 (4.11 g, 97%) as a colourless, amorphous solid; Rf 0.63 (66% EtOAc–hexane);

FTIR (film) max: 2923, 1747, 1717, 1690, 1596, 1351 cm–1

; (New C=O, no OH); m/z (CI) 509

[M+H]+ (Found [M+H]


+, 509.1746). Found C, 63.80;

H, 5.63; N, 5.37%. C27H28N2O6S requires C, 63.76; H, 5.55; N, 5.51%;

δH (400 MHz, CDCl3) 8.03 (2 H, app. d, J 8.5 Hz, meta-Ts), 7.79 (1 H, app. d, J 8.0 Hz, 12),

7.38––7.23 (4H, m, ortho-Ts, 9, and 11), 7.17 (1H, t, J 7.5 Hz, 10), 6.88 (1H, s, 2),

6.49 (1H, ddd, J 10.0, 6.0, 1.5 Hz, 15), 5.98 (1H, d, J 10.0 Hz, 14), 5.14 (1H, dd, J 11.5, 4.0 Hz,

5), 4.08 (1H, dd, J 11.5, 4.5 Hz, 17a), 3.84 (1H, dd, J 11.5, 8.5 Hz, 17b), 3.76 (3H, s, N1Me),

3.36 (1H, dd, J 14.0, 4.0 Hz, 6a), 3.23––3.03 (3H, m, 20a, 20b and 6b), 2.89––2.82 (1H, m, 16),

2.43 (3H, s, TsMe), 2.10 (3H, s, 18);

δC (100 MHz, CDCl3) 200.3 (C19), 166.6 (C21), 161.2 (C3), 145.0 (para-Ts), 140.0 (C15),

137.2 (C13), 136.2 (ipso-Ts), 129.4 (meta-Ts), 129.2 (ortho-Ts), 127.9 (C2), 127.5 (C8), 126.7

Experimental

163

(C14), 122.0 (C11), 119.5 (C10), 119.1 (C12), 109.5 (C9), 109.3 (C7), 63.6 (C17), 56.9 (C5),

49.2 (C20), 36.6 (C16), 32.9 (N1Me), 30.3 (C6), 30.1 (C18), 21.7 (TsMe).

(4aR*,8S*,8aR*,Z)-4-(1-Hydroxyethylidene)-8-((1-methylindol-3-yl)methyl)-7-

tosyltetrahydro-1H-pyrano[3,4-c]pyridine-3,6(4H,7H)-dione (91)

To a solution of malonate ester 113 (3.48 g, 6.85 mmol, 1.0 equiv.) in THF (23 mL) at rt was

added DBU (2.0 mL, 13.7 mmol, 2.0 equiv.). The reaction mixture was allowed to stir at rt for

12 h, saturated aqueous NH4Cl (2 mL) was added and the aqueous layer extracted with EtOAc

(3×30 mL) and CH2Cl2 (2×50 mL). The organic layers were washed with brine, combined, dried


EtOAc–hexane) yielded (4aR*,8S*,8aR*,Z)-4-(1-hydroxyethylidene)-8-((1-methylindol-3-

yl)methyl)-7-tosyltetrahydro-1H-pyrano[3,4-c]pyridine-3,6(4H,7H)-dione 91 (3.34 g, 93%) as an

amorphous solid; Rf 0.24 (33% EtOAc–hexane); FTIR (film) max: 3058, 2923, 2855, 2252,

1690, 1636, 1612, 1597 cm–1

; m/z (CI) 509 [M+H]+ (Found [M+H]

+, 509.1741. C27H28N2O6S

requires [M+H]+, 509.1746);

δH (400 MHz, CDCl3) 13.72 (1H, s, 19-OH), 7.94 (2H, d, J 8.5 Hz, meta-Ts),

7.72 (1H, d, J 8.0 Hz, 9), 7.38––7.30 (3H, m, ortho-Ts and 12), 7.27 (1H, t, J 8.0 Hz, 11),

7.17 (1H, t, J 8.0 Hz, 10), 6.94 (1H, s, 2), 4.78 (1H, ddd, J 8.0, 3.0, 2.0 Hz, 5),

4.21 (1H, ddd, J 11.5, 4.5 1.5 Hz, 17a), 4.03 (1H, t, J 12.0 Hz, 17b), 3.78 (3H, s, N1Me),

3.54 (1H, dd, J 15.0, 4.0 Hz, 6a), 3.21 (1H, dd, 15.0, 10.0 Hz, 6b), 3.16––3.07 (1H, m, 15),

2.61––2.46 (2H, m, 14a and 16), 2.45 (3H, s, TsMe), 2.17 (1H, dd, J 19.0, 10.5 Hz, 14b),

1.74 (3H, s, 18);

Experimental

164


135.7 (ipso-Ts), 129.5 (meta-Ts), 129.1 (ortho-Ts), 128.2 (C2), 127.7 (C8), 122.3 (C11), 119.8

(C10), 118.6 (C12), 109.7 (C9), 108.3 (C7), 96.2 (C20), 66.9 (C17), 57.3 (C5),

36.6 (C14), 32.9 (N1Me), 31.5 (C6), 26.0 (C15), 21.7 (TsMe), 18.0 (C18).

Pentacyclic lactone (85)

To a solution of lactam–lactone 91 (0.87 g, 1.71 mmol, 1.0 equiv.) in THF (5.7 mL) at


stirred at –78°C for 3 h. The reaction was quenched with wet Et2O (2 mL) and allowed to warm

to rt, then trifluoromethanesulfonic acid (0.16 mL, 1.71 mmol, 1.0 equiv.) was added and the

solution allowed to stir for 30 minutes. Saturated aqueous Rochelle salt (10 mL) and EtOAc (30

mL) were added, and the resulting suspension stirred vigorously at rt overnight. Saturated

aqueous NaHCO3 (10 mL) was added, and the aqueous phase extracted with EtOAc (3×50 mL)

and CH2Cl2 (2×50 mL). The organic phases were washed with brine, combined, dried over

MgSO4, and filtered. Concentration under reduced pressure and chromatography (33% EtOAc–

hexane) yielded pentacyclic lactone 85 (0.77 g, 91%) as an amorphous solid. Data is in

accordance with that previously reported (Page 158).57

Experimental

165

3.1.7 Procedures from attempted synthesis of functionalised pentacyclic lactone (Sections 2.2.3-

2.2.6)

(4aR*,8S*,8aR*,Z)-4-(1-Hydroxyethylidene)-8-((1-methylindol-3-yl)methyl)tetrahydro-1H-

pyrano[3,4-c]pyridine-3,6(4H,7H)-dione (124)

To a solution of naphthalene (0.91 g, 7.01 mmol, 8.0 equiv.) in THF (24 mL) at rt was added

sodium (163 mg, 7.01 mmol, 8.0 equiv.) and the reaction mixture stirred at rt for 2 h. The

resulting dark green\blue solution was cooled to –78°C and added to a solution of lactam–lactone

91 (450 mg, 0.890 mmol, 1.0 equiv.) in THF (5 mL) at –78°C. The reaction mixture was stirred

at –78°C for 2 h. Saturated aqueous NH4Cl (12 mL) was added and the solution allowed to warm

slowly from –78°C to rt. The aqueous layer was then extracted with EtOAc (3×50 mL), the

organic layers were washed with brine, combined, dried over MgSO4 and filtered. Concentration

under reduced pressure and chromatography (100% EtOAc) yielded (4aR*,8S*,8aR*,Z)-4-(1-

hydroxyethylidene)-8-((1-methylindol-3-yl)methyl)tetrahydro-1H-pyrano[3,4-c]pyridine-

3,6(4H,7H)-dione 124 (312 mg, 99%) as a pale yellow oil; Rf 0.10 (100% EtOAc); FTIR (film)

max: 3212, 2917, 2247, 1635, 1475, 1423, 1240, 1328 cm–1

; m/z (ES) 355 [M+H]+ (Found

[M+H]+, 355.1642. C20H22N2O4 requires [M+H]

+, 355.1658);

δH (400 MHz, CDCl3) 13.84 (1H, s, 21), 7.51 (1H, d, J 8.0 Hz, 9), 7.33 (1H, d, J 8.0 Hz, 12),

7.26 (1H, t, J 8.0 Hz, 11), 7.13 (1H, t, J 8.0 Hz, 10), 6.93 (1H, s, 2), 6.35 (1H, s, N4H), 4.38 (1H,

t, J 12.0 Hz, 17a), 4.22 (1H, ddd, J 12.0, 5.0, 1.5 Hz, 17b), 3.78 (3H, s, N1Me), 3.56––3.48 (1H,

m, 5), 3.12––3.00 (3H, m, 6a, 6b and 15), 2.54 (1H, dd, J 18.0, 6.0 Hz, 14a), 2.47––2.40 (1H, m,

16), 2.24 (1H, dd, J 18.0, 12.0 Hz, 14b), 1.99 (3H, s, 18);

Experimental

166

δC (100 MHz, CDCl3) 176.9 (C19), 171.4 (C21), 169.5 (C3), 137.2 (C13), 127.9 (C2), 127.3

(C8), 122.3 (C11), 119.5 (C10), 118.3 (C12), 109.7 (C9), 108.6 (C7), 96.4 (C20), 67.1 (C17),

52.4 (C5), 34.1 (C6), 33.5 (C16), 32.8 (N1Me), 26.8 (C15), 18.2 (C18).

(4S*,4aR*,8S*,8aR*)-4-Acetyl-4-methyl-8-((1-methylindol-3-yl)methyl)tetrahydro-1H-

pyrano[3,4-c]pyridine-3,6(4H,7H)-dione (126a) and (4S*,4aR*,8S*,8aR*)-4-acetyl-4,7-

dimethyl-8-((1-methylindol-3-yl)methyl)tetrahydro-1H-pyrano[3,4-c]pyridine-3,6(4H,7H)-

dione (126b)

To a solution of deprotected N4H lactam 124 (31.0 mg, 0.061 mmol, 1.0 equiv.) in THF

(1 mL) at –78°C was added KHMDS (0.5 M in toluene; 0.15 mL, 0.073 mmol, 1.2 equiv.) and

the solution stirred at –78°C for 1 h. Iodomethane (0.5 mL, 0.067 mmol, 1.1 equiv.) was added

and the solution allowed to warm slowly from –78°C to rt overnight. The reaction was quenched

with wet Et2O (2 mL), 10% aqueous citric acid (5 mL) was added and the aqueous layer

extracted with CH2Cl2 (3×30 mL) and EtOAc (3×30 mL). The organic layers were washed with

brine, combined, dried over MgSO4 and filtered. Concentration under reduced pressure and

chromatography (25→50% EtOAc–hexane) yielded (4S*,4aR*,8S*,8aR*)-4-acetyl-4-methyl-8-

((1-methylindol-3-yl)methyl)tetrahydro-1H-pyrano[3,4-c]pyridine-3,6(4H,7H)-dione 126a and

(4S*,4aR*,8S*,8aR*)-4-acetyl-4,7-dimethyl-8-((1-methylindol-3-yl)methyl)tetrahydro-1H-

pyrano[3,4-c]pyridine-3,6(4H,7H)-dione 126b (28.8 mg, 93%) as amorphous solids;

Experimental

167

(4S*,4aR*,8S*,8aR*)-4-Acetyl-4-methyl-8-((1-methylindol-3-yl)methyl)tetrahydro-1H-

pyrano[3,4-c]pyridine-3,6(4H,7H)-dione (126a)

Rf 0.65 (50% EtOAc–hexane); FTIR (film) max: 3284, 2918, 2249, 1736, 1706, 1659, 1474

cm–1

; m/z (ES) 369 [M+H]+ (Found [M+H]

+, 369.1800. C21H24N2O4 requires [M+H]

+,

369.1814);

δH (400 MHz, CDCl3) 7.51 (1H, d, J 8.0 Hz, 9), 7.34 (1H, d, J 8.0 Hz, 12), 7.27 (1H, t, J 8.0 Hz,

11), 7.15 (1H, t, J 8.0 Hz, 10), 6.93 (1H, s, 2), 6.10 (1H, s, N4H), 4.41 (1H, dd, J 12.0, 6.5 Hz,

17a), 4.30 (1H, t, J 12.0 Hz, 17b), 3.77 (3H, s, N1Me), 3.76––3.70 (1H, m, 5), 3.03 (1H, dd,

J 14.5, 5.5 Hz, 6a), 2.87 (1H, dd, J 14.5, 9.0 Hz, 6b), 2.66 (1H, dd, J 15.5, 11.5 Hz, 14a),

2.60––2.34 (3H, m, 16, 15 and 14b), 2.31 (3H, s, 22), 1.54 (3H, s, 18);

δC (100 MHz, CDCl3) 205.9 (C19), 171.1 (C21), 170.3 (C3), 137.3 (C13), 127.7 (C2), 127.3

(C8), 122.4 (C11), 119.6 (C10), 118.3 (C12), 109.7 (C9), 108.0 (C7), 67.7 (C17), 58.0 (C20),

51.8 (C5), 36.0 (C15), 33.9 (C16), 32.8 (N1Me), 31.0 (C6), 30.9 (C14), 28.9 (C22), 23.1 (C18).

(4S*,4aR*,8S*,8aR*)-4-Acetyl-4,7-dimethyl-8-((1-methylindol-3-yl)methyl)tetrahydro-1H-

pyrano[3,4-c]pyridine-3,6(4H,7H)-dione (126b)

Experimental

168

Rf 0.65 (50% EtOAc–hexane). FTIR (film) max: 2922, 1732, 1707, 1659, 1468 cm–1

; m/z (ES)

383 [M+H]+ (Found [M+H]

+, 383.1958. C22H26N2O4 requires [M+H]

+, 383.1971).


11), 7.16 (1H, t, J 8.0 Hz, 10), 6.88 (1H, s, 2), 4.35 (1H, t, J 12.0 Hz, 17a), 4.16 (1H, dd, J 12.0,

6.5 Hz, 17b), 3.79 (3H, s, N1Me), 3.43 (1H, dd, J 10.5, 4.0 Hz, 5), 3.37 (1H, dd, J 14.5, 4.0 Hz,

6a), 3.14 (3H, s, N4Me), 2.86 (1H, dd, J 14.5, 10.5 Hz, 6b), 2.61––2.54 (2H, m, 15 and 16), 2.50

(1H, dd, J 17.5, 6.0 Hz, 14a), 2.33 (3H, s, 22), 2.29 (1H, dd, J 17.5, 12.0 Hz, 14b), 1.41 (3H, s,

18);

δC (100 MHz, CDCl3) 206.2 (C19), 171.2 (C21), 166.5 (C3), 137.2 (C13), 127.2 (C2), 122.4

(C11), 119.5 (C10), 118.2 (C12), 109.8 (C9), 109.0 (C7), 68.1 (C17), 60.0 (C5), 57.6 (C20),

34.6 (C16), 34.6 (N4Me), 32.8 (N1Me), 31.3 (C14), 30.3 (C22), 28.8 (C15), 28.3 (C14), 24.5

(C18).

N4-Demethyl pentacyclic lactone (85a)

To a solution of naphthalene (157 mg, 1.23 mmol, 8.0 equiv.) in THF (2 mL) at rt was added

sodium (28.2 mg, 1.23 mmol, 8.0 equiv.) and the reaction mixture stirred at rt for 2 h. The

resulting dark green\blue solution was cooled to –78°C and added to a solution of pentacyclic

lactone 85 (75.4 mg, 0.153 mmol, 1.0 equiv.) in THF (1 mL) at –78°C. The reaction mixture was

stirred at –78°C for 2 h. Saturated aqueous NH4Cl (12 mL) was added and the solution allowed

to warm slowly from –78°C to rt. The aqueous layer was then extracted with EtOAc (3×50 mL),

the organic layers were washed with brine, combined, dried over MgSO4 and filtered.

Concentration under reduced pressure and chromatography (50→100% EtOAc–hexane) yielded

N4-demethyl pentacyclic lactam 85a (47.6 mg, 92%) as a pale yellow gum; Rf 0.10 (100%

Experimental

169

EtOAc); FTIR (film) max: 2928, 2247, 1729, 1635, 1469, 1420 cm–1

; m/z (CI) 356 [M+NH4]+

(Found [M+NH4]+, 356.1969. C20H22N2O3 requires [M+NH4]

+, 356.1974).

δH (400 MHz, CDCl3) 7.47 (1H, dd, J 12.5, 8.0 Hz, ArH), 7.31 (1H, dd, J 8.0, 5.5 Hz, ArH),

7.28––7.20 (1H, m, ArH), 7.13 (1H, q, J 8.0 Hz, ArH), 6.12 (0.6H, t, J 3.0 Hz, 3a), 5.18 (0.4H,

t, J 3.0 Hz, 3b), 5.06 (0.4H, d, J 7.5 Hz, 5b), 4.55––4.26 (2H, m, 17a and 17b), 4.18 (0.6H, d, J

7.0 Hz, 5a), 3.71 (1.2H, s, N1Meb), 3.70 (1.8H, s, N1Mea), 3.40 (1H, ddd, J 17.0, 10.0, 7.5 Hz,

6a), 2.86 (0.6H, d, J 16.0 Hz, 6ba), 2.73 (0.4H, d, J 16.0 Hz, 6bb), 2.57 (1H, ddd, J 18.0, 11.5,

6.5 Hz, 14aa), 2.37––2.21 (3H, m, 14aa and 14b), 2.20 (1.2H, s, TsMeb), 2.11 (1.8H, s, TsMea),

2.08––1.91 (1.2H, m, 18a), 1.74––1.62 (1.8H, m, 18b);

δC (100 MHz, CDCl3) 169.6 (C19), 169.4 (C19), 168.9 (C21), 168.4 (C21), 137.2 (C13), 137.1

(C13), 133.2 (C2), 131.8 (C2), 125.8 (C8), 125.8 (C8), 122.2 (C11), 121.9 (C11), 119.8 (C10),

119.6 (C10), 118.4 (C12), 117.9 (C12), 109.3 (C9), 109.2 (C9), 108.8 (C7), 106.8 (C7), 68.4

(C17), 68.0 (C17), 50.1 (C5), 49.0 (C3), 43.8 (C5), 43.0 (C3), 38.2 (C16), 37.7 (C16),

34.3 (C15), 34.2 (C15), 31.7 (C14), 30.5 (C14), 29.4 (N1Me), 29.4 (N1Me), 27.5 (C6), 26.0

(C6), 24.5, 21.6 (C18), 21.1 (C18).


yl)methyl 2-(2-methyl-1,3-dioxolan-2-yl)acetate (130)

To a stirred solution of β-ketoester 113 (48.0 mg, 0.094 mmol, 1.0 equiv.) and

1,2-bis(trimethylsiloxy)ethane (0.05 mL, 0.190 mmol, 2.0 equiv.) in CH2Cl2 (5 mL) at –78°C

was added trimethylsilyl trifluoromethanesulfonate (1 drop) and the reaction mixture was stirred

Experimental

170

at –78°C for 3 h. Saturated aqueous NH4Cl (2 mL) was added and the aqueous layer extracted

with CH2Cl2 (3×30 mL). The organic layers were washed with brine, combined, dried over

MgSO4 and filtered. Concentration under reduced pressure and chromatography (50% EtOAc–

hexane) yielded ((2S*,3R*)-2-((1-Methylindol-3-yl)methyl)-6-oxo-1-tosyl-1,2,3,6-

tetrahydropyridin-3-yl)methyl 2-(2-methyl-1,3-dioxolan-2-yl)acetate 130 (48.3 mg, 93%) as an

amorphous solid; Rf 0.25 (50% EtOAc–hexane); FTIR (film) max: 3059, 2987, 1738. 1689.

1598, 1473 cm–1

; m/z (ES) 575 [M+Na]+ (Found [M+Na]

+, 575.1804. C29H32N2O7S requires

[M+Na]+, 575.1828);

δH (400 MHz, CDCl3) 8.02 (2H, d, J 8.0 Hz, meta-Ts), 7.77 (1H, d, J 8.0 Hz, 12), 7.73––7.20

(4H, m, ortho-Ts, 11 and 9) 7.16 (1H, td, J 7.5, 1.0 Hz, 10), 6.89 (1H, s, 2), 6.49 (1H, ddd,

J 10.0, 6.0, 1.5 Hz, 15), 5.95 (1H, dd, J 10.0, 0.5 Hz, 14), 5.16 (1H, dd, J 11.0, 4.0 Hz, 5),

4.04––3.71 (10H, m, N1Me, 17a, 17b, 22a, 22b, 23a and 23b), 3.37 (1H, dd, J 14.0, 4.0 Hz, 6a),

3.12 (1H, dd, J 14.0, 11.0 Hz, 6b), 2.84 (1H, dt, J 14.0, 5.0 Hz, 16), 2.45––2.30 (5H, m, TsMe,

20a and 20b), 1.36 (3H, s, 18);

δC (100 MHz, CDCl3) 169.0 (C21), 161.2 (C3), 144.9 (para-Ts), 140.3 (C15), 137.2 (C13),

136.3 (ipso-Ts), 129.3 (ortho-Ts), 129.2 (para-Ts), 127.8 (C2), 127.6 (C8), 126.6 (C14), 122.0

(C11), 119.4 (C10), 119.2 (C12), 109.4 (C7), 64.8 (C22), 64.7 (C23), 63.0 (C17), 57.0 (C5),

43.5 (C20), 36.4 (C16), 32.8 (N1Me), 30.4 (C6), 24.3 (C18), 21.7 (TsMe).

Tetracyclic indolomorphan lactam (133)

Rf 0.15 (50% EtOAc–hexane); 279.0–283.6°C; FTIR (film) max: 2989, 1736, 1695, 1613, 1597,

1470 cm–1

; m/z (CI) 575 [M+Na]+ (Found [M+Na]

+, 575.1840. C29H32N2O7S requires [M+Na]

+,

575.1828).

Experimental

171


7.30––7.20 (4H, m, meta-Ts, 11 and 9), 7.12 (1H, td, J 8.0, 1.0 Hz, 10), 5.17 (1H, br. s, 5), 4.27

(2H, d, J 7.5 Hz, 17a and 17b), 4.03 (4H, br. s, 22, 23), 3.63 (3H, s, N1Me), 3.44 (1H, dd, J 17.0,

1.5 Hz, 6a), 3.36 (1H, t, J 4.0 Hz, 15), 3.19 (1H, dd, J 17.0, 4.0 Hz, 6b), 2.79––2.65 (3H, m, 20a,

20b and 16), 2.70 (1H, dd, J 18.5, 5.5 Hz, 14a), 2.48 (1H, d, J 18.5 Hz, 14b), 2.37 (3H, s, TsMe),

1.56 (3H, s, 18);

δC (100 MHz, CDCl3) 169.3 (C21), 168.1 (C3), 144.8 (para-Ts), 137.6 (C13), 136.3

(ipso-Ts), 136.2 (C2), 129.3, (ortho-Ts) 128.9 (meta-Ts), 126.6 (C8), 121.99 (C11), 119.6

(C10), 118.5 (C12), 109.1 (C9), 107.6 (C19), 104.0 (C7), 64.9 (22 and 23), 63.23 (C17), 53.6

(C5), 44.2 (C20), 37.6 (C16), 35.8 (C14), 30.5 (C6) 29.0 (N1Me), 26.6 (C15), 24.7 (C18), 21.66

(TsMe).

((2R*,3R*)-2-(2-Hydroxyethoxy)-6-oxo-1-tosyl-1,2,3,6-tetrahydropyridin-3-yl)methyl 2-(2-

methyl-1,3-dioxolan-2-yl)acetate (132)

Rf 0.35 (50% EtOAc–hexane). FTIR (film/cm-1

) max: 2983, 2885, 1739, 1691, 1597, 1349, 1168

cm–1

; m/z (ES) 506 [M+Na]+ (Found [M+Na]

+, 506.1265. C22H29NO9S requires [M+Na]

+,

506.1461).

δH (400 MHz, CDCl3) 7.96 (2H, d, J 8.0 Hz, meta-Ts), 7.31 (2H, d, J 8.0 Hz, ortho-Ts),

6.54 (1H, ddd, J 10.0, 6.0, 1.5 Hz, 15), 5.91 (1H, dd, J 10.0, 0.5 Hz, 14), 4.94 (1H, ddt, J 9.0,

5.0, 1.0 Hz, 5), 4.14 (1H, dd, J 11.5, 4.5 Hz, 17a), 4.02––3.98 (4H, br. m, 22 and 23), 3.92 (1H,

dd, J 11.5, 8.5 Hz, 17b), 3.62 (1H, dd, J 10.0, 5.0 Hz, 6a), 3.59––3.44 (3H, m, 6b and 24), 3.15–

–3.07 (1H, m, 16), 2.67 (2H, s, 20), 1.60 (1H, s, OH), 1.53 (3H, s, 18), 1.18 (3H, t, J 7.0 Hz, 25);

Experimental

172


129.3 (ortho-Ts), 129.2 (para-Ts), 126.4 (C14), 107.4 (C19), 70.2 (C6), 66.8 (C24), 64.8 (C22

and C23), 63.1 (C17), 55.3 (C5), 43.9 (C20), 35.4 (C16), 24.5 (C18), 21.7 (TsMe), 15.1 (C25).

Allylic diol (135)

To a solution of pentacyclic lactone 85 (34.0 mg, 0.069 mmol, 1.0 equiv.) in THF (1 mL) at


stirred under reflux at 70°C for 1 h. Saturated aqueous Rochelle salt (5 mL) and EtOAc (15 mL)

were added and the resulting suspension stirred vigorously at rt overnight. The aqueous phase

was extracted with EtOAc (3×50 mL) and CH2Cl2 (3×20 mL) and the organic phases were

combined, dried over MgSO4 and filtered. Concentration under reduced pressure and preparative

thin layer chromatography (50% EtOAc–hexane) yielded allylic diol 135 (15.2 mg, 46%) as an

amorphous solid; Rf 0.10 (66% EtOAc–hexane); FTIR (film) max: 3401, 2921, 1469, 1338, 1160

cm–1

; m/z (ES) 481 [M+H]+ (Found [M+H]


+,

481.2161).

δH 7.32 (2H, app. d, J 8.0 Hz, ortho-Ts), 7.28––7.22 (1H, m, 9), 7.19––7.13 (2H, m, 12 and 11),

7.01 (1H, t, J 7.5 Hz, 10), 6.77 (2H, app. d, J 8.0 Hz, meta-Ts), 5.56 (1H, q, J 7.0 Hz, 19), 5.40

(br. t, J 3.5 Hz, 3), 4.59 (1H, d, J 8.5 Hz, 5), 4.09––3.92 (3H, m, 21a, 21b and 17a), 3.70 (1H,

dd, J 11.0, 5.0, 17b), 3.67 (3H, s, N1Me), 3.16––3.08 (1H, m, 14a), 2.84 (1H, dd, J 16.5, 8.0 Hz,

6a), 2.56 (1H, td, J 13.5, 4.5 Hz, 14b), 2.47––2.40 (2H, m, 6b and OH), 2.02 (3H, s, TsMe)

1.73––1.63 (2H, m, 15 and OH), 1.48 (3H, d, J 7.0 Hz, 18);

δC (100 MHz, CDCl3) δ 143.3 (para-Ts), 138.9 (C13), 136.7 (C20), 136.0 (ipso-Ts), 132.3 (C2),

128.8 (meta-Ts), 126.4 (ortho-Ts), 126.0 (C8) 125.8 (C19), 121.5 (C11), 119.1 (C10), 117.9

(C12), 108.8 (C9), 107.8 (C7), 66.7 (C21), 60.6 (C17), 49.4 (C5), 48.2 (C3), 47.9 (C15), 29.5

(C14), 29.0 (N1Me), 24.8 (C6), 21.1 (TsMe), 13.4 (C18).

Experimental

173

Exomethylene compound (137)

To a solution of oxalyl chloride (1.0 M in CH2Cl2; 0.06 ml, 0.059 mmol, 1.4 equiv.) at –78°C

was added DMSO (0.01 mL, 0.12 mmol, 2.8 equiv.) and the solutions stirred at –78°C for 15

min. Allylic diol 135 was added (~0.85M in CH2Cl2; 0.5 mL, 0.042 mmol, 1.0 equiv.) and the

solution allowed to warm from –78°C to –10°C over 2 h. Et3N (0.1 mL, excess) was added at

–10°C and the solution allowed to warm from –10°C to rt over 15 min. Water (2 mL) was added

and the aqueous layer was extracted with CH2Cl2 (3×20 mL), the organic layers were combined,


chromatography (50% EtOAc–hexane) yielded exomethylene aldehyde 137 (18.8 mg, 97%) as

colourless amorphous solid; Rf 0.40 (50% EtOAc–hexane); FTIR (film) max: 2921, 1706, 1469,

1338, 1160 cm–1

; m/z (ES) 481 [M+H]+ (Found [M+H]

+, 461.1904. C27H28N2O3S requires

[M+H]+, 461.1899).

δH (500 MHz, CDCl3) 9.89 (1H, br. t, 21), 7.37 (2H, app. d, J 8.0 Hz, ortho-Ts), 7.28––7.23

(2H, m, 9 and 12), 7.19––7.14 (1H, m, 11), 7.02 (1H, t, J 7.5 Hz, 10), 6.78 (2H, app. d, J 8.0 Hz,

meta-Ts), 5.72 (1H, q, J 7.0 Hz, 19), 5.38 (br. t, J 3.5 Hz, 3), 4.92 (1H, br. d, J 8.5 Hz, 5), 4.34

(1H, d, J 11.0 Hz, 17a), 4.08 (1H, d, J 11.0 Hz, 17b), 3.68 (3H, s, N1Me), 3.23––3.17 (1H, m,

14a), 3.08 (1H, dd, J 16.5, 8.0 Hz, 6a), 2.60––2.55 (1H, m, 14b), 2.50 (1H, d, J 16.5 Hz, 6b),

2.05––2.01 (1H, m, 15), 1.98 (3H, s, TsMe), 1.48 (3H, d, J 7.0 Hz, 18);

δC (100 MHz, CDCl3) 201.8 (C21), 143.7 (para-Ts), 136.7 (C13), 136.3 (ipso-Ts), 135.4 (C20),

132.0 (C19), 130.6 (C2), 128.7 (meta-Ts), 126.6 (ortho-Ts), 125.8 (C8), 121.8 (C11), 119.3

(C3), 117.8 (C12), 108.9 (C9), 106.9 (C7), 57.7 (C16), 49.1 (C5), 48.7 (C17), 48.1 (C3), 29.9

(C15), 29.2 (C14), 29.0 (N1Me), 24.6 (C6), 21.1 (TsMe), 13.7 (C18).

Experimental

174

trans-4-Methoxy-3-buten-2-one (142)

To a solution of β-ketodimethylacetal 188 (10.0 mL, 76.2 mmol, 1.0 equiv.) in MeOH (5 mL) at

rt was added sodium methoxide (80.0 mg, 1.54 mmol, 0.02 equiv.) and the solution heated to

120°C in the microwave for 1 h. Concentration under reduced pressure and distillation under

reduced pressure yielded a 72:28 ratio of starting material 188 to trans-4-methoxy-3-buten-2-one

142 as colourless oil (9.6 mL) as a colourless oil. Data is in accordance with that previously

reported by Brannock et al.125

(5R*,6S*)-5-((1-Methoxy-3-oxobutoxy)methyl)-6-((1-methylindol-3-yl)methyl)-1-tosyl-5,6-

dihydropyridin-2(1H)-one (141)

A solution of lactam alcohol 90 (80.0 mg, 0.185 mmol, 1.0 equiv.) and trans-4-methoxy-3-

buten-2-one (0.74 mL, 1.85 mmol, 10 equiv.) in CH2Cl2 (1 mL) at –78°C was added 1 drop of

triflic acid and the solution stirred at –78°C for 2 h. Saturated NaHCO3 (2 mL) was added and

the aqueous layer extracted with EtOAc (3×10 mL) and CH2Cl2 (3×10 mL). The organics were


flash column chromatography (40→60% EtOAc–hexane) yielded the (5R*,6S*)-5-((1-Methoxy-

3-oxobutoxy)methyl)-6-((1-methylindol-3-yl)methyl)-1-tosyl-5,6-dihydropyridin-2(1H)-one 141

as a 1:1 mixture of epimers (94.1 mg, 97%) as a colourless amorphous solid; Rf 0.31 (66%

Experimental

175

EtOAc–hexane); FTIR (film) max: 2921, 1712, 1689, 1472, 1350, 1168 cm–1

; m/z (ES) 547

[M+Na]+ (Found [M+Na]

+, 547.1873. C28H32N2O6S requires [M+Na]

+, 547.1879);

δH (400 MHz, CDCl3) 8.06––7.99 (2H, m, ArH), 7.77––7.68 (2H, m, ArH), 7.35––7.21 (4H, m,

ArH), 7.18––7.12 (1H, m, ArH), 6.88 (1H, d, J 8.0 Hz, ArH), 6.54––6.47 (1H, m, 15),

5.93––5.88 (1H, 2×d, J 10.0 Hz, 14), 5.15 (1H, 2×dd, J 11.0, 4.0 Hz, 5), 4.73 (0.5H, t, J 5.5 Hz,

21a), 4.65 (0.5H, t, J 5.5 Hz, 21b), 3.76 and 3.75 (3H, s, N1Me), 3.51 (0.5H, dd, J 10.0, 5.5 Hz,

17aa), 3.42––3.28 (2.5H, m, 17ab, 17ba and 6a), 3.28––3.21 (2H, 17bb and OMea), 3.16––3.05

(2.5H, 6b and OMeb), 2.76 (1H, dt, J 10.0, 6.0 Hz, 16), 2.58 (1H, d, J 6.0 Hz, 20a), 2.54 (0.5H,

d, J 5.5 Hz, 20ba), 2.46 (0.5H, d, J 5.5 Hz, 20bb), 2.43––2.41 (3H, TsMe), 2.09 (1.5H, s, 18a),

1.93 (1.5H, s, 18b);

δH (400 MHz, CDCl3) 205.4 (C19), 205.3 (C19), 161.6 (C3), 161.5 (C3), 144.8 (para-Ts), 141.9

(C15), 137.1 (ArC), 136.5 (ipso-Ts), 129.3 (meta-Ts), 129.2 (meta-Ts), 127.8 (ArC), 125.9

(C14), 121.9 (ArC), 119.4 (ArC), 119.4 (ArC), 119.2 (ArC), 119.0 (ArC), 109.6 (ArC), 109.3

(ArC), 101.1 (C21), 100.7 (C21), 66.7 (C17), 66.0 (C17), 57.2 (C5), 56.7 (C5), 53.8 (OMe),

53.7 (OMe), 47.2 (C20), 47.0 (C20), 37.7 (C16), 37.5 (C16), 32.7 (N1Me), 31.1 (C18), 31.0

(C18), 30.1 (C6), 30.0 (C6), 21.7 (TsMe).

3.1.8 Procedures from total synthesis of type A macroline-related alkaloid alstonerinal 138

(Section 2.2.8)

Type a methyl ester (148)

To a solution of the enol 85 (281 mg, 0.571 mmol, 1.0 equiv.) in MeOH:CH2Cl2 (1:1) (2 mL) at

rt was added CSA (13 mg, 0.057 mmol, 0.1 equiv.) and trimethylorthoformate (1.20 mL, 1.14

mmol, 2.0 equiv.) and the reaction heated under reflux for 72 h. The reaction mixture was then

cooled to rt after which saturated NaHCO3 was added dropwise. The aqueous layers were then

Experimental

176

extracted with CH2Cl2 (3×30 mL), and the combined organics washed with brine, dried over

MgSO4 and filtered. Concentration under reduced pressure and purification via preparative thin

layer chromatography (50% EtOAc–Hexane) yielded N4-(±)-tosylalstonerinal precursor 148

(194 mg, 67%) as an amorphous solid; Rf 0.50 (50% EtOAc–hexane); FTIR (film) max: 2935,

1702, 1612, 1469, 1343 cm–1

; m/z (ES) 507 [M+H]+ (Found [M+H]

+, 507.1970. C28H30N2O5S

requires [M+H]+, 507.1954);

δH (400 MHz, CDCl3) 7.41––7.33 (2H, app. d, J 8.0 Hz, ortho-Ts), 7.29––7.22 (1H, m, 12),

7.22––7.09 (2H, td, J 8.0, 1.5 Hz, 9 and 11), 7.05––6.95 (1H, td, J 7.0, 1.0 Hz, 10),

6.83––6.76 (2H, app. d, J 8.0 Hz, meta-Ts), 5.26 (1H, br. t, J 3.0 Hz, 3), 4.35––4.13 (3H, m,

5, 17a and 17b), 3.67 (3H, s, OMe), 3.51 (3H, s, N1Me), 2.90 (1H, dd, J 16.0, 7.0 Hz, 6a),

2.72 (1H, br. dt, J 12.0, 3.0 Hz, 15), 2.47 (1H, d, J 16.0 Hz, 6b), 2.19 (3H, s, TsMe)

2.08––2.16 (1H, m, 16), 2.01 (3H, s, 18), 1.92––2.01 (2H, m, 14);


132.1 (C2), 128.2 (meta-Ts), 126.4 (ortho-Ts), 126.2 (C8), 121.4 (C11), 119.0 (C10), 117.8

(C12), 108.9 (C9), 107.0 (C7), 104.1 (C20), 65.8 (C17), 50.9 (OMe), 49.6 (C5), 48.6 (C3), 38.5

(C16), 32.9 (C14), 29.2 (N1Me), 25.7 (C6), 25.4 (C15), 21.1 (TsMe), 20.6 (C18).

N4H-(±)-Alstonerinal precursor (191)


sodium (9.0 mg, 0.40 mmol, 8.0 equiv.) and the reaction mixture stirred at rt for 1 h. The dark

green\blue solution was then cooled to –78°C and (~0.1 M in THF; 1.00 mL, 0.400 mmol, 8.0

equiv.) was added to a solution of N4-Ts protected type A macroline methyl ester 148 (24 mg,

0.05 mmol, 1.0 equiv.) in THF (1 mL). The reaction mixture was stirred at

–78°C for 30 min. Saturated aqueous NaHCO3 (2 mL) was added and the solution allowed to

Experimental

177

warm slowly from –78°C to rt over 2 hours. The aqueous layer was then extracted with EtOAc

(3×30 mL) and CH2Cl2 (2×50 mL), the organic layers were washed with brine, combined, dried


EtOAc) yielded N4H-(±)-alstonerinal precursor 191 (12.9 mg, 92%) as a pale yellow oil; Rf 0.45

(25% MeOH–EtOAc); FTIR (film) max: 3329, 2923, 1733, 1704, 1613, 1469, 1239 cm–1

; m/z

(ES) 353 [M+H]+ (Found [M+H]

+, 353.1856. C21H24N2O3 requires [M+H]

+, 353.1865);


11), 7.11 (1H, t, J 8.0 Hz, 10), 4.40 (1H, t, J 11.5 Hz, 17a), 4.25 (1H, t, J 3.5 Hz, 3), 4.15 (1H,

ddd, J 10.5, 4.0, 1.5 Hz, 17b), 3.64 (3H, s, N1Me), 3.52––3.44 (4H, s, OMe and 5), 3.26 (1H, dd,

J 16.5, 7.0 Hz, 6a), 2.74––2.60 (2H, m, 6b and 15), 2.19 (3H, d, J 0.5 Hz, 18), 2.08––2.01

(1H, m, 14a), 1.96––1.84 (2H, m, 16 and 14b);

δC (100 MHz, CDCl3) 168.5 (C21), 165.2 (C19), 136.9 (C13), 126.8 (C2) 121.1 (C11), 118.9

(C10), 117.9 (C12), 108.9 (C9), 107.1 (C7), 105.1 (C20), 67.0 (C17), 50.8 (OMe), 48.5 (C5),

46.7 (C3), 38.0 (C16), 32.1 (C14), 29.0 (N1Me), 28.8 (C6), 26.1 (C15), 20.5 (C18).

N4-Methyl-(±)-alstonerinal precursor (150)

To a stirred solution of secondary N4H amine 191 (12.0 mg, 0.034 mmol, 1.0 equiv.) in THF (0.5

mL) at –78°C was added Hünig’s Base (0.02 mL, 0.102 mmol, 3.0 equiv.) and iodomethane

(0.002 mL, 0.05 mmol, 1.4 equiv.) and the solution allowed to warm slowly from –78°C to rt

overnight. Water (2 mL) was added to the resulting cloudy solution and the aqueous layer

extracted with CH2Cl2 (4×10 mL). The combined organic layers were dried over MgSO4, filtered

and concentrated under reduced pressure. Purification via preparative thin layer chromatography

yielded N4-Methyl-(±)-alstonerinal precursor 150 as a pale yellow oil (9.9 mg, 81%); Rf 0.67

Experimental

178

(20% MeOH–EtOAc); FTIR (film) max: 2928, 1703, 1613, 1469, 1434, 1076 cm–1

; m/z (CI) 367

[M+H]+ (Found [M+H]

+, 367.2032. C22H26N2O3 requires [M+H]

+, 367.2022);

δH (400 MHz, CDCl3) 7.51 (1H, br. d, J 8.0 Hz, 12), 7.33 (1H, br. d, J 8.0 Hz, 9),

7.21 (1H, td, J 8.0, 1.0 Hz, 11), 7.12 (1H, td, J 8.0, 1.0 Hz, 10), 4.85 (1H, t, J 12.0 Hz, 17a),

4.22 (1H, ddd, J 12.0, 4.0, 2.0 Hz, 17b), 3.90 (1H, br. s, 3), 3.65 (3H, s, N1Me),

3.50 (3H, s, OMe), 3.32 (1H, dd, J 16.0, 7.0 Hz, 6a), 3.07 (1H, br. d, J 7.0 Hz, 5), 2.88 (1H, m,

15), 2.49 (1H, d, J 16.0 Hz, 6b), 2.43 (3H, d, 4J 1.0 Hz, 18), 2.32 (3H, br. s N4Me), 2.05 (1H, m,

16), 1.99 (2H, m, 14a and 14b);

δC (100 MHz, CDCl3) 170.1 (C19), 167.2 (C21), 137.1 (C13), 133.2 (C2), 127.6 (C20), 126.7

(C8), 120.8 (C11), 118.8 (C10), 118.0 (C12), 108.7 (C9), 106.3 (C7), 68.8 (C17), 62.1 (OMe),

54.8 (C22), 54.7 (C5), 53.7 (C3), 41.6 (N4Me), 39.8 (C16), 29.9 (C14), 29.0 (N1Me), 25.8

(C15), 22.5 (C6), 15.2 (C18).

Over-reduced-(±)-alstonerinal precursor (151)

To a solution of N4-methyl-(±)-alstonerinal precursor 150 (9.3 mg, 0.025 mmol, 1.0 equiv.) in

toluene (0.5 mL) at –92°C was added DIBAL (1.0 M in toluene; 0.05 mL, 0.05 mmol, 2.0

equiv.). and the solution stirred at –92°C for 1 h. Wet Et2O (2 mL) was added and the reaction

mixture was allowed to warm slowly from –92°C to rt. Saturated aqueous Rochelle salt (10 mL)

and EtOAc (10 mL) were added, and the resulting suspension stirred vigorously at rt overnight.

The aqueous phase extracted with EtOAc (3×20 mL) and CH2Cl2 (2×20 mL). The organic phases

were washed with brine (20 mL), combined, dried over MgSO4 and filtered. Concentrated under

reduced pressure and purification via preparative thin layer chromatography (3% MeOH–EtOAc)

yielded over-reduced-(±)-alstonerinal precursor 151 (8.4 mg, 99%) as an amorphous solid; Rf

Experimental

179

0.39 (5% MeOH–EtOAc); FTIR (film) max: 3350, 2913, 1670, 1469, 1380 cm–1

; m/z (ES) 339

[M+H]+ (Found [M+H]

+, 339.2079. C21H26N2O2 requires [M+H]

+, 339.2073);



3.99 (1H, ddd, J 12.0, 4.0, 2.0 Hz, 17b), 3.96––3.82 (3H, m, 3 and 21a), 3.85 (1H, d, J 12.0 Hz,

21b), 3.64 (3H, s, N1Me), 3.30 (1H, dd, J 16.0, 7.0 Hz, 6a), 3.09 (1H, br. d, J 7.0 Hz, 5), 2.49

(1H, d, J 16.0 Hz, 6b), 2.33 (3H, s, N4Me), 2.08 (1H, dt, J 12.0, 6.0 Hz, 15), 1.96––1.86 (3H, m,

14a, 14b and 16), 1.83 (3H, d 4J 1.0 Hz, 18);

δC (125 MHz, CDCl3) 150.5 (C19), 137.5 (C13), 133.4 (C2), 127.2 (C8), 120.9 (C11), 118.9

(C10), 118.0 (C9), 109.9 (C20), 108.9 (C12), 106.2 (C7), 66.6 (C21), 62.0 (C17), 55.1 (C5),

53.7 (C3), 41.8 (N4Me), 40.6 (C16), 33.5 (C14), 29.1 (N1Me), 27.0 (C15), 22.9 (C6), 16.3

(C18). Data is in accordance with that previously reported by T. Kam et al.101

(±)-Alstonerinal (138)

To a solution of alcohol 151, (9.0 mg, 0.026 mmol, 1.0 equiv.) and pyridine (0.007 mL, 0.079

mmol, 3.0 equiv.) at 0°C was added Dess–Martin periodinane (16.8 mg, 0.040 mmol, 1.5 equiv.)

and the solution stirred at 0°C for 2 h. Water (1 mL) was added and the aqueous phase extracted

with EtOAc (3×10 mL) and CH2Cl2 (2×10 mL). The organic phases were washed with brine (20

mL), combined, dried over MgSO4 and filtered. Concentrated under reduced pressure and

purification via preparative thin layer chromatography (5% MeOH–EtOAc) yielded (±)-

alstonerinal 138 (1.2 mg, 13%) as a colourless oil; Rf 0.2 (5% MeOH–EtOAc);

δH (500 MHz, CDCl3) 9.65 (1H, s, 21), 7.44 (1H, br. d, J 8.0 Hz, 9), 7.31 (1H, br. d, J 8.0 Hz,

12), 7.20 (1H, td, J 8.0, 1.0 Hz, 11), 7.11 (1H, td, J 8.0, 1.0 Hz, 10), 4.46 (1H, t, J 12.0 Hz, 17a),

4.18 (1H, ddd, J 12.0, 4.0, 2.0 Hz, 17b), 3.86 (1H, br. d, 3), 3.63 (3H, s, N1Me), 3.31 (1H, dd,

Experimental

180

J 16.0, 7.0 Hz, 6a), 3.09 (1H, br. d, J 7.0 Hz, 5), 2.61 (1H, dt, J 12.0, 6.0 Hz, 15), 2.49 (1H, d,

J 16.0 Hz, 6b), 2.33 (3H, s, N4Me,), 2.15 (3H, s, 18), 2.12 (1H, ddd, J 12.0, 5.0, 3.0 Hz, 14a),

1.89––1.83 (1H, m, 16), 1.79 (1H, td, J 12.0, 3.0 Hz, 14b). Data is in accordance with that

previously reported by T. Kam et al.101

3.1.9 Procedures from synthesis of N4-tosyl macroline 152 (Section 2.2.8)

Z-N4-(±)-Tosylmacroline precursor (147)

To a solution of the enol 85 (51 mg, 0.104 mmol, 1.0 equiv.) in MeOH:CH2Cl2 (1:1) (0.5 mL) at

rt was added CSA (3 mg, 0.010 mmol, 0.1 equiv.) and trimethylorthoformate (0.16 mL, 0.155

mmol, 1.5 equiv.) and the reaction stirred for 16 h. Saturated NaHCO3 was added dropwise and

the aqueous layers were then extracted with CH2Cl2 (3×30 mL), and the combined organics


purification via preparative thin layer chromatography (50% EtOAc–Hexane) yielded Z-N4-(±)-

tosylmacroline precursor 147 as an amorphous solid (16.3 mg, 31%) and N4-(±)-

tosylalstonerinal precursor 148 (31.6 mg, 60%) as an amorphous solid; Rf 0.15 (50% EtOAc–

Hexane); FTIR (film) max: 2932, 1687, 1584, 1468 cm–1

; m/z (ES) 507 [M+H]+ (Found [M+H]

+,

507.1941. C28H30N2O5S requires [M+H]+, 507.1954);

δH (400 MHz, CDCl3) 7.36 (2H, app. d, J 8.0 Hz, ortho-Ts), 7.24––7.29 (1H, m, 12),

7.14––7.20 (2H, m, 9 and 11), 7.02 (1H, td, J 8.0, 1.0 Hz, 10), 6.80 (2H, app. d, J 8.0 Hz,

meta-Ts), 5.27 (1H, br. t, J 3.0 Hz, 3), 4.66 (1H, t, J 12.0 Hz, 17a), 4.24––4.33 (2H, m, 17b and

5), 3.67 (3H, s, N1Me), 3.51 (3H, s, OMe), 3.02––3.10 (1H, m, 15), 2.90 (1H, dd, J 16.5, 7.5 Hz,

6a), 2.44––2.49 (1H, m, 6b), 2.44 (3H, s, TsMe), 1.97––2.15 (6H, m, 18, 14a, 14b and 16);

Experimental

181



(C12), 108.8 (C9), 107.2 (C7), 104.6 (C20), 67.1 (C17), 55.1 (OMe), 49.6 (C5), 48.5 (C3), 39.2

(C16), 29.9 (C14), 29.1 (N1Me), 25.9 (C6), 25.3 (C15), 21.1 (TsMe), 15.3 (C18).

N4-Tosyl-(±)-macroline (152)

To a solution of type B macroline methyl enol 147 (39.0 mg, 0.076 mmol, 1.0 equiv.) in CH2Cl2

(0.75 mL) at –78°C was added DIBAL (1.0 M in toluene; 0.084 mL, 0.084 mmol, 1.1 equiv.).

and the solution stirred at –78°C for 1 h. Wet Et2O (2 mL) was added and the reaction mixture

was allowed to warm slowly from –78°C to rt. Saturated aqueous Rochelle salt (10 mL) and

EtOAc (10 mL) were added, and the resulting suspension stirred vigorously at rt overnight. The

aqueous phase extracted with EtOAc (3×20 mL) and CH2Cl2 (2×20 mL). The organic phases

were washed with brine (20 mL), combined, dried over MgSO4 and filtered. Concentrated under

reduced pressure and purification via preparative thin layer chromatography (50% EtOAc–

hexane) yielded N4-tosyl-(±)-macroline 152 (11.7 mg, 32% + 55% 147 recovery) as an


1339, 116 cm–1

; m/z (ES) 479 [M+H]+ (Found [M+H]

+, 479.1985. C27H30N2O4S requires

[M+H]+, 479.2005);

δH (500 MHz, CDCl3) 7.31 (2H, d, J 8.0 Hz, ortho-Ts), 7.22 (1H, d, J 8.0 Hz, 12), 7.18 (1H, d,

J 8.0 Hz, 9), 7.15 (1H, td, J 8.0, 1.0 Hz, 11), 7.01 (1H, dt, J 8.0, 1.0 Hz, 10), 6.77 (2H, d, J 8.0

Hz, meta-Ts), 6.09 (1H, d, J 1.0 Hz, 21a), 5.66 (1H, d, J 1.5 Hz, 21b), 5.44 (1H, t, J 3.5 Hz, 3),

4.60 (1H, br. d, J 8.0 Hz, 5), 3.90 (1H, td, J 11.0, 5.5 Hz, 17a), 3.65 (3H, s, N1Me), 3.39 (1H,

ddd, J 11.0, 7.0, 4.5 Hz, 17b), 3.20 (1H, dt, J 13.5, 4.0 Hz, 15), 2.78 (1H, dd, J 16.5, 8.0 Hz, 6a),

2.58 (1H, d, J 16.5 Hz, 6b), 2.37 (1H, td, J 13.0, 4.0 Hz, 14a), 2.26 (3H, s, 18), 2.19––2.14 (2H,

m, 16 and OH), 2.03 (3H, s, TsMe) 1.45 (1H, dt, J 13.0, 3.0 Hz, 14b);

Experimental

182



(C10), 118.3 (C12), 108.7 (C9), 108.1 (C7), 59.6 (C17), 48.5 (C5), 48.0 (C21), 44.5 (C16), 30.2

(C14), 29.3 (C15), 29.2 (N1Me), 26.3 (C18), 24.3 (C6), 21.1 (TsMe).

Z-N4H-(±)-Macroline precursor (189)


sodium (8.0 mg, 0.319 mmol, 8.0 equiv.) and the reaction mixture stirred at rt for 1 h.

The dark green\blue solution was then cooled to –78 °C and (~0.1 M in THF; 2.0 mL, 0.200

mmol, 5.0 equiv.) was added to a solution of N4-Ts protected type B macroline methyl enol 147

(20.3 mg, 0.040 mmol, 1.0 equiv.) in THF (1 mL). The reaction mixture was stirred at –78°C for

2 h. Saturated aqueous NaHCO3 (2 mL) was added and the solution allowed to warm slowly

from –78°C to rt. The aqueous layer was then extracted with EtOAc (3×30 mL) and CH2Cl2

(2×50 mL), the organic layers were washed with brine, combined, dried over MgSO4 and

filtered. Concentration under reduced pressure and chromatography (100% EtOAc) yielded Z-

N4H-(±)-macroline precursor 189 (12.1 mg, 86%) as a pale yellow oil; Rf 0.11 (100% EtOAc);

FTIR (film) max: 2935, 1702, 1612, 1469, 1343 cm–1

; m/z (CI) 353 [M+H]+ (Found [M+H]

+,

353.1856. C22H25N2O3 requires [M+H]+, 353.1685);

δH (400 MHz, CDCl3) 7.41––7.33 (2H, app. d, ortho-Ts), 7.29––7.22 (1H, m, 12),

7.22––7.09 (2H, td, J 7.0, 1.5 Hz, 9 and 11), 7.05––6.95 (1H, td, J 7.0, 1.0 Hz, 10),

6.83––6.76 (2H, app. d, J 8.0 Hz, meta-Ts), 5.26 (1H, br. t, J 3.0 Hz, 3), 4.35––4.13 (3H, m, 5,

17a and 17b), 3.67 (3H, s, OMe), 3.51 (3H, s, N1Me), 2.90 (1H, dd, J 16.0, 7.0 Hz, 6a),

2.72 (1H, br. dt, J 12.0, 3.0 Hz, 15), 2.47 (1H, d, J 16.0 Hz, 6b), 2.19 (3H, s, TsMe)

2.08––2.16 (1H, m, 16), 2.01 (3H, s, 18), 1.92––2.01 (2H, m, 14a and 14b);

Experimental

183

δC (100 MHz, CDCl3) 168.2 (C19), 165.5 (C21), 143.4 (ortho-Ts), 136.9 (C13), 136.2 (ipso-Ts),


(C12), 108.9 (C9), 107.0 (C7), 104.1 (C20), 65.8 (C17), 50.9 (OMe), 49.6 (C5), 48.6 (C3), 38.5

(C16), 32.9 (C14), 29.2 (N1Me), 25.7 (C6), 25.4 (C15), 21.1 (TsMe), 20.6 (C18).

N4-Methyl-(±)-macroline precursor (153)

To a stirred solution of type B macroline methyl enol N4H amine 189 (12.0 mg, 0.034 mmol, 1.0

equiv.) in THF (0.5 mL) at –78°C was added Hünig’s Base (0.02 mL, 0.102 mmol, 3.0 equiv.)

and iodomethane (0.002mL, 0.05 mmol, 1.4 equiv.) and the solution allowed to warm slowly

from –78°C to rt overnight. Water (2 mL) was added to the resulting cloudy solution and the

aqueous layer extracted with CH2Cl2 (4×10 mL). The combined organic layers were dried over

MgSO4, filtered and concentrated under reduced pressure. Purification via preparative thin layer

chromatography yielded N4-methyl-(±)-macroline precursor 153compound as a pale yellow oil

(9.9 mg, 81%); Rf 0.67 (20% MeOH–EtOAc); FTIR (film) max: 2921, 1701, 1613, 1469, 1379

cm–1

; m/z (ES) 367 [M+H]+ (Found [M+H]

+, 367.2036. C22H26N2O3 requires [M+H]

+,

367.2022);



4.11 (1H, ddd, J 12.0, 4.0, 2.0 Hz, 17b), 3.90 (1H, br. t, 3), 3.65 (3H, s, N1Me),

3.50 (3H, s, OMe), 3.32 (1H, dd, J 16.0, 7.0 Hz, 6a), 3.12 (1H, br. d, J 7.0 Hz, 5),

2.47––2.59 (2H, m, 15 and 6b), 2.33 (3H, d, 4J 1.0 Hz, 18), 2.19 (3H, br. s, N4Me),

2.05 (1H, m, 16), 1.86––1.97 (2H, m, 14a and 14b);

Experimental

184

δC (100 MHz, CDCl3) 168.6 (C19), 165.2 (C21), 133.3 (C2), 126.7 (C8), 120.8 (C10), 118.8

(C11), 118.0 (C9), 108.9 (C12), 106.1 (C7), 67.4 (C17), 54.8 (C3), 53.9 (C5), 41.7 (C16), 38.5

(C14), 29.0 (N1Me), 25.4 (C15), 24.9 (N4Me), 22.8 (C6), 22.7 (C18).

3.1.10 Procedures from progress towards total synthesis of alstolactone (Section 2.2.9) and

improved route to N4-tosyl-anhydromacrosalhine-methine 157 (Section 2.2.12)

Z-Pentacyclic triflate (154)

To a solution of enol 85 (155 mg, 0.315 mmol, 1.0 equiv.) in CH2Cl2 (3 mL) at –78°C was added

Hünig’s base (0.11 mL, 0.630 mmol, 2.0 equiv.) and triflic anhydride

(0.08 mL, 0.473 mmol, 1.5 equiv.) and the reaction mixture stirred at –78°C for 30 min.

H2O (1 mL) was added and the aqueous layer extracted with CH2Cl2 (3×30 mL). The combined

organics were washed with brine, dried over MgSO4 and filtered. Concentration under reduced

pressure and flash column chromatography (20% EtOAc–hexane) yielded the Z-pentacyclic

triflate 154 (124 mg, 63%) as a white amorphous solid; Rf 0.23 (33% EtOAc–hexane); FTIR

(film) max: 3528, 3305, 3060, 2952, 1738, 1156 cm–1

; m/z (CI) 625 [M+H]+ (Found [M+H]

+,

625.1300. C28H27F3N2O7S2 requires [M+H]+, 625.1290).

δH (400 MHz, CDCl3) 7.36 (2H, app. d, J 8.0 Hz, ortho-Ts), 7.28––7.15 (3H, m, 9, 11 and 12),

7.04 (1H, td, J 7.0, 1.0 Hz, 10), 6.82 (2H, app. d, J 8.0 Hz, meta-Ts), 5.37 (1H, br. s, 3), 4.78

(1H, t, J 12.0 Hz, 17a), 4.47 (1H, ddd, J 12.0, 5, 1.0 Hz, 17b), 4.29 (1H, br. d, J 7.0, 5), 3.68

(3H, s, N1Me), 2.89––3.00 (2H, m, 6a and 15), 2.51 (1H, d, J 16.0 Hz, 6b), 2.30––2.40 (2H, m,

14a and 16), 2.03 (3H, s, TsMe), 1.75 (3H, s, 18), 1.69 (1H, ddd, J 14.0, 4.5, 3.0 Hz, 14b);


130.8 (C8), 129.0 (meta-Ts), 126.4 (ortho-Ts), 125.8 (C8), 122.2 (C11), 120.1 (ipso-Ts), 119.6

Experimental

185

(C10), 118.0 (C9), 109.1 (C12), 107.4 (C7), 67.7 (C17), 49.0 (C5), 47.6 (C3), 38.8 (C16), 30.3

(C14) 29.5 (C15), 29.3 (N1Me), 25.0 (C6), 21.2 (TsMe), 18.2 (C18);

δF (100 MHz, CDCl3) –74.49 (CF3).

N4-Tosyl-alstolactone (155)

To a solution of palladium(II)acetate (4.0 mg, 0.018 mmol, 0.1 equiv.), Ph3P (14.0 mg, 0.054

mmol, 0.3 equiv.), Et3N (0.08 mL, 0.537 mmol, 3.0 equiv.) and formic acid (0.015 mL, 0.358

mmol, 2.0 equiv.) in a microwave vial was added enol triflate 154 (112 mg, 0.0.179 mmol, 1.0

equiv.) and the solution heated at 80°C for 20 min in the microwave.

Concentration under reduced pressure and chromatography (20% EtOAc–hexane) yielded N4-

tosyl-alstolactone 155 (52.8 mg, 73%) as a white amorphous solid; Rf 0.16 (66% EtOAc–

hexane); FTIR (film) max: 3051. 2920, 1710, 1630, 1597, 1469, 1159 cm–1

; m/z (ES) 477

[M+H]+ (Found [M+H]


+, 476.1848);

δH (400 MHz, CDCl3) 7.36 (2H, app. d, J 8.0 Hz, ortho-Ts), 7.33––7.10 (4H, m, 9, 11, 12 and

19) 7.04 (1H, td, J 8.0, 1.0 Hz, 10), 6.82 (2H, app. d, J 8.0 Hz, meta-Ts), 5.33 (1H br. s, 3), 4.77

(1H, t, J 12.0 Hz, 17a), 4.39 (1H, ddd, J 12.0, 5.0, 2.0 Hz, 17b), 4.30 (1H, br. d, J 7.0 Hz, 5),

3.69 (3H, s, N1Me), 2.89––3.00 (2H, m, 6a and 15), 2.50 (1H, d, J 16.0 Hz, 6b), 2.30––2.18 (2H,

m, 14a and 16), 2.03 (3H, s, TsMe), 1.74 (1H, ddd, J 14.0, 5.0, 3.0 Hz, 14b), 1.46 (3H, d, J 7.0

Hz, 18);

δC (100 MHz, CDCl3) 164.9 (C21), 143.7 (C19), 143.3 (para-Ts), 136.9 (C13) , 135.9

(ipso-Ts), 131.3 (C2), 128.9 (meta-Ts), 127.6 (C20), 126.4 (ortho-Ts), 126.0 (C8) 121.9 (C11),

119.4 (C10), 118.0 (C12), 109.0 (C9), 107.5 (C7), 67.1 (C17), 49.2 (C5), 48.0 (C3), 39.0 (C16),

30.5 (C14), 29.3 (N1Me), 26.6 (C15), 25.3 (C6), 21.1 (TsMe), 13.9 (C18).

Experimental

186

(4aR*,8S*,8aR*,E)-4-Ethylidene-8-((1-methylindol-3-yl)methyl)-7-tosyltetrahydro-1H-


To a solution of enol triflate 161 (109 mg, 0.17 mmol, 1.0 equiv.), palladium(II)acetate (4.0 mg,

0.017 mmol, 0.1 equiv.), Ph3P (14.0 mg, 0.051 mmol, 0.3 equiv.), and formic acid (0.04 mL,

0.068 mmol, 4.0 equiv.) in DMF (1 mL) in a microwave vial was added Et3N (0.4 mL, 0.85

mmol, 5.0 equiv.) and the solution heated at 80°C for 30 min in the microwave.

Immediate chromatography (20% EtOAc–hexane), concentration under reduced pressure and

DMF removal by washing a solution of the title compound in EtOAc (25 mL) sequentially with

water (25 mL), 5% aqueous LiCl solution (25 mL), water (25 mL) and brine (25 mL) yielded

(4aR*,8S*,8aR*,E)-4-ethylidene-8-((1-methylindol-3-yl)methyl)-7-tosyltetrahydro-1H-

pyrano[3,4-c]pyridine-3,6(4H,7H)-dione 167 (71.2 mg, 85%) as a white amorphous solid; Rf

0.19 (50% EtOAc–hexane); FTIR (film) max: 3057, 2924, 2855, 1716, 1695, 1638, 1612, 1596,

1477 cm–1

; m/z (CI) 493 [M+H]+ (Found [M+H]+, 493.1790. C27H28N2O5S requires [M+H]+,

493.1797).


7.37––7.23 (4H, m, meta-Ts and 12, then 11), 7.16 (1H, t, J 8.0 Hz, 10), 7.08 (1H, q, J 8.0 Hz,

19), 6.96 (1H, s, 2), 4.81––4.74 (1H, m, 5), 4.21––4.04 (2H, m, 17a and 17b), 3.78 (3H, s,

N1Me), 3.56 (1H, dd, J 14.5, 3.5 Hz, 6a), 3.46––3.37 (1H, m, 15), 3.20 (1H, dd, J 14.5, 10.0 Hz,

6b), 2.64––2.50 (2H, m, 16 and 14a), 2.44 (3H, s, TsMe), 2.19 (1H, dd, J 18.5, 10.5 Hz, 14b),

1.63 (3H, d, J 7.0 Hz, 18);

Experimental

187


135.7 (ipso-Ts), 129.5 (ortho-Ts), 129.2 (meta-Ts), 128.1 (C2), 127.7 (C11), 127.3 (C8), 122.3

(C20), 119.8 (C10), 118.6 (C12), 109.7 (C9), 108.4 (C7), 66.7 (C17), 57.7 (C5), 34.6 (C14),

32.9 (N1Me), 32.4 (C16), 31.7 (C6), 26.5 (C15), 21.7 (TsMe), 13.8 (C18).

(4aR*,8S*,8aR*,E)-4-Ethylidene-8-((1-methylindol-3-yl)methyl)-7-tosyltetrahydro-1H-


To a solution of enol triflate 161 (109 mg, 0.170 mmol, 1.0 equiv.), palladium(II)acetate (4.0 mg,

0.017 mmol, 0.1 equiv.), Ph3P (14.0 mg, 0.051 mmol, 0.3 equiv.), and formic acid (0.04 mL,

0.068 mmol, 4.0 equiv.) in DMF (1 mL) in a microwave vial was added Et3N (0.4 mL, 0.850

mmol, 5.0 equiv.) and the solution heated at 80°C for 30 min in the microwave.

Immediate chromatography (20% EtOAc–hexane), concentration under reduced pressure and

DMF removal by washing a solution of the title compound in EtOAc (25 mL) sequentially with

water (25 mL), 5% aqueous LiCl solution (25 mL), water (25 mL) and brine (25 mL) yielded

(4aR*,8S*,8aR*,E)-4-ethylidene-8-((1-methylindol-3-yl)methyl)-7-tosyltetrahydro-1H-

pyrano[3,4-c]pyridine-3,6(4H,7H)-dione 167 (71.2 mg, 85%) as a white amorphous solid; Rf

0.19 (50% EtOAc–hexane); FTIR (film) max: 3057, 2924, 2855, 1716, 1695, 1638, 1612, 1596,

1477 cm–1

; m/z (CI) 493 [M+H]+ (Found [M+H]+, 493.1790. C27H28N2O5S requires [M+H]+,

493.1797).


7.37––7.23 (4H, m, meta-Ts and 12, then 11), 7.16 (1H, t, J 8.0 Hz, 10), 7.08 (1H, q, J 8.0 Hz,

19), 6.96 (1H, s, 2), 4.81––4.74 (1H, m, 5), 4.21––4.04 (2H, m, 17a and 17b), 3.78 (3H, s,

Experimental

188

N1Me), 3.56 (1H, dd, J 14.5, 3.5 Hz, 6a), 3.46––3.37 (1H, m, 15), 3.20 (1H, dd, J 14.5, 10.0 Hz,

6b), 2.64––2.50 (2H, m, 16 and 14a), 2.44 (3H, s, TsMe), 2.19 (1H, dd, J 18.5, 10.5 Hz, 14b),

1.63 (3H, d, J 7.0 Hz, 18);


135.7 (ipso-Ts), 129.5 (ortho-Ts), 129.2 (meta-Ts), 128.1 (C2), 127.7 (C11), 127.3 (C8), 122.3

(C20), 119.8 (C10), 118.6 (C12), 109.7 (C9), 108.4 (C7), 66.7 (C17), 57.7 (C5), 34.6 (C14),

32.9 (N1Me), 32.4 (C16), 31.7 (C6), 26.5 (C15), 21.7 (TsMe), 13.8 (C18).

3.1.11 Procedures from synthesis of N4-tosyl anhydromacrosalhine-methine 157 (Section 2.2.10)

N4-Tosyl-anhydromacrosalhine-methine (157)

To a solution of N4-tosylalstolactone 154 (28.6 mg, 0.060 mmol, 1.0 equiv.) in CH2Cl2 (1 mL) at


stirred at –78°C for 3h. Wet Et2O (5 mL) was added and the reaction mixture was allowed to

warm slowly from –78°C to rt. Saturated aqueous Rochelle salt

(5 mL) and EtOAc (15 mL) were added and the resulting suspension stirred vigorously at rt

overnight. Saturated NaHCO3 (10 mL) was added and the aqueous phase extracted with EtOAc

(3×50 mL). The organic phases were combined, dried over MgSO4 and filtered. Concentration

under reduced pressure and preparative thin layer chromatography

(50% EtOAc–hexane) yielded N4-tosyl-anhydromacrosalhine-methine 157 (26.0 mg, 94%) as a

white amorphous solid; Rf 0.35 (50% EtOAc–hexane); FTIR (film) max: 3420, 2890, 1630, 1470

cm–1

; m/z (CI) 461 [M+H]+ (Found [M+H]


+,

561.1899).

δH (400 MHz, CDCl3) 7.40 (2H, app. d, J 8.0 Hz, ortho-Ts), 7.28––7.25 (1H, m, 9),

7.20––7.15 (2H, m, 11 and 12), 7.03 (1H, td, J 8.0, 1.0 Hz, 10), 6.84 (2H, app. d, J 8.0 Hz,

Experimental

189

meta-Ts), 6.47 (1H, s, 21), 6.0.0 (1H, dd, J 17.5, 11.0 Hz, 19), 5.29 (1H, br. t, J 3.5 Hz, 3),

4.57 (1H, dd, J 11.5, 0.5 Hz, 18a), 7.39 (1H, d, J 17.5 Hz, 18b), 4.33 (1H, d, J 7.5 Hz, 5),

4.26 (1H, t, J 11.5 Hz, 17a), 4.11 (1H, ddd, J 11.5, 4.0, 1.5 Hz, 17b), 3.67 (3H, s, N1Me),

2.93 (1H, dd, J 16.5, 7.5 Hz, 6a), 2.57 (1H, t, J 4.5 Hz, 15), 2.52 (1H, d, J 16.5 Hz, 6b),

2.17 (1H, ddd, J 14.0, 5.0, 3.0 Hz, 14a), 2.10––2.00 (5H, m, 14b, 16, TsMe);

δC (400 MHz, CDCl3) 145.6 (C21), 143.4 (para-Ts), 136.9 (C13), 136.3 (ipso-Ts), 133.7 (C19),


(C12), 115.9 (C20), 108.9 (C9), 107.4(C7), 106.7 (C18), 65.3 (C17), 49.7 (C5), 48.5 (C3), 38.5

(C16), 32.1 (C14), 29.2 (N1Me), 25.8 (C6), 23.5 (C15), 21.1 (TsMe).

3.1.12 Procedures from total synthesis of alstonerine 4 (Section 2.2.11)

N4-Tosylalstonerine (134)

To a solution of pentacyclic triflate 154 (26.0 mg, 0.042 mmol, 1.0 equiv.) in CH2Cl2 (1 mL) at


stirred at –78°C for 3 h. Wet Et2O (5 mL) was added and the reaction mixture was allowed to

warm slowly from –78°C to rt. Saturated aqueous Rochelle salt (10 mL) and EtOAc (10 mL)

were added, and the resulting suspension stirred vigorously at rt overnight. Saturated aqueous

NaHCO3 (10 mL) was added, and the aqueous phase extracted with EtOAc (3×20 mL) and

CH2Cl2 (2×20 mL). The organic phases were washed with brine (20 mL), combined, dried over

MgSO4, filtered and concentrated under reduced pressure to yield the intermediate lactol as an

amorphous, colourless solid.

Purification by chromatography (50% EtOAc–hexane) yielded N4-tosylalstonerine 134 (19.8 mg,

100%) as an amorphous solid. For data see final approach (Page 191).

Experimental

190

(Z)-1-((4aR*,8S*,8aR*)-8-((1-Methylindol-3-yl)methyl)-3,6-dioxo-7-tosyl-1H-pyrano[3,4-

c]pyridin-4(3H,4aH,5H,6H,7H,8H,8aH)ylidene)ethyl trifluoromethanesulfonate (161)

To a solution of enol 91 (31.0 mg, 0.061 mmol, 1.0 equiv.) in THF (1 mL) at –78°C was added

KHMDS (0.5 M in toluene; 0.15 mL, 0.073 mmol, 1.2 equiv.) and the solution stirred at –78°C

for 1 h. A solution of PhNTf2 (0.13 M in THF; 0.5 mL, 0.067 mmol, 1.1 equiv.) was added and

the solution allowed to warm slowly from –78°C to rt overnight. The reaction was quenched

with wet Et2O (2 mL), 10% aqueous citric acid (5 mL) was added and the aqueous layer

extracted with CH2Cl2 (3×30 mL) and EtOAc (3×30 mL). The organic layers were washed with

brine, combined, dried over MgSO4 and filtered. Concentration under reduced pressure and

chromatography (25→50% EtOAc–hexane) yielded the title compound (28.8 mg, 74%) as an


1596, 1476, 1415, 1354 cm–1

; m/z (CI) 663 [M+Na]+ (Found [M+Na]

+, 663.1062.

C28H27N2O8S2F3 requires [M+Na]+, 663.1059);

δH (400 MHz, CDCl3) 7.98 (2H, d, J 8.5 Hz, ortho-Ts), 7.83 (1H, d, J 8.0 Hz, 12),

7.37––7.32 (3H, m, meta-Ts, 9), 7.29 (1H, t, J 8.0 Hz, 11), 7.19 (1H, t, J 8.0 Hz, 10),

6.99 (1H, s, 2), 4.87 (1H, ddd, J 8.0, 3.0, 2.0 Hz, 5), 4.20 (1H, ddd, J 11.5, 4.5 1.5 Hz, 17a),

4.15––4.06 (1H, m, 17b), 3.87––3.79 (1H, m, 15), 3.78 (3H, s, N1Me), 3.65 (1H, dd, J 15.0, 4.0

Hz, 6a), 3.00 (1H, dd, J 15.0, 10.0 Hz, 6b), 2.90 (1H, dd, J 19.0, 8.0 Hz, 14a), 2.55 (1H, m, 16),

2.52 (3H, s, 18), 2.45 (3H, s, TsMe), 2.34 (1H, dd, J 19.0, 9.5 Hz, 14b);

δC (100 MHz, CDCl3) 166.5 (C3), 161.8 (C21), 159.8 (C19), 145.5 (ipso-Ts), 137.3 (C13),

135.5 (para-Ts), 129.5 (meta-Ts), 129.3 (ortho-Ts), 128.0 (C2), 127.2 (C8), 122.3 (C11), 121.5

Experimental

191

(C20), 119.7 (C10), 119.0 (C12), 109.6 (C9), 108.2 (C7), 67.8 (C17), 57.1 (C5),

34.2 (C14), 32.8 (N1Me), 31.9 (C6), 31.2 (C16) 28.2 (C15), 21.8 (TsMe), 19.7 (C18);

δF NMR (100 MHz, CDCl3) –73.8 (CF3).

N4-Tosylalstonerine (134)

To a solution of the enol triflate derivative of 161 prepared as described above (200 mg, 0.312

mmol, 1.0 equiv.) in CH2Cl2 (2 mL) at –78°C was added DIBAL (1.0 M in toluene; 0.78 mL,

0.781 mmol, 2.5 equiv.) and the solution stirred at –78°C for 2.25 h. Wet Et2O (5 mL) was added

and the reaction mixture was allowed to warm slowly from –78°C to rt. Saturated aqueous

Rochelle salt (10 mL) and EtOAc (10 mL) were added, and the resulting suspension stirred

vigorously at rt overnight. Saturated aqueous NaHCO3 (10 mL) was added, and the aqueous

phase extracted with EtOAc (3×20 mL) and CH2Cl2 (2×20 mL). The organic phases were

washed with brine (20 mL), combined, dried over MgSO4, filtered and concentrated under

reduced pressure to yield the intermediate lactol as an amorphous, colourless solid.

The intermediate lactol was then taken up in wet CH2Cl2 (10 mL) and stirred at rt for 1 h. The

dark brown solution was then filtered over basic alumina to give crude

N4-tosylalstonerine 134 as an amorphous, colourless solid. Purification by chromatography

(50% EtOAc–hexane) yielded N4-tosylalstonerine 134 (146 mg, 98%) as an amorphous solid; Rf

0.56 (50% EtOAc–hexane); FTIR (film) max: 2988, 2301, 1619, 1449, 2338, 2276, 1261 cm–1

;



+, 477.1848);

Experimental

192

δH (400 MHz, CDCl3) 7.55 (1H, s, 21), 7.35 (2H, d, J 8.0 Hz, ortho-Ts),

7.25 (1H, d, J 8.0 Hz, 9), 7.18–7.10 (2H, m, 12 and 11), 6.99 (1H, td, J 8.0, 1.0 Hz, 10),

6.79 (2H, d, J 8.0 Hz, meta-Ts), 5.24 (1H, br. t, J 3.0 Hz, 3), 4.35––4.25 (3H, m, 17a, 17b and

5), 3.67 (3H, s, N1Me), 2.88 (1H, dd, J 16.5, 8.0 Hz, 6a), 2.84––2.76 (1H, m, 15),

2.47 (1H, d, J 16.5, 6b), 2.17 (1H, ddd, J 12.0, 5.0, 3.0 Hz, 14a), 2.10 (3H, s, 18),

2.00 (3H, s, TsMe), 1.98––1.85 (2H, m, 14b and 16);

δC (100 MHz, CDCl3) 195.2 (C19), 157.5 (C21), 143.4 (para-Ts), 136.9 (C13),

136.1 (ipso-Ts), 131.9 (C2), 128.8 (meta-Ts), 126.3 (ortho-Ts), 126.1 (C8), 121.5 (C11), 120.2

(C20), 119.0 (C10), 117.7 (C12), 108.9 (C9), 106.8 (C7), 66.2 (C17), 49.4 (C5),

48.5 (C3), 38.0 (C15), 32.3 (C14), 29.2 (N1Me), 25.6 (C6), 25.0 (C18), 22.8 (C16), 21.1

(TsMe).

N4-Demethylalstonerine (190)

To a solution of naphthalene (200 mg, 1.60 mmol) in THF (16 mL) at rt was added sodium

(40.0 mg, 1.60 mmol) and the reaction mixture stirred at rt for 1 h. The resulting dark green\blue

solution was cooled to –78°C and (~0.1 M in THF; 0.33 mL, 0.031 mmol, 5.0 equiv.) was added

to a solution of 134 (31.3 mg, 0.066 mmol, 1.0 equiv.) in THF (3 mL) at

–78°C. The reaction mixture was stirred at –78°C for 2 h. Saturated aqueous NaHCO3

(3 mL) was added and the solution allowed to warm slowly from –78°C to rt. The aqueous layer

was then extracted with EtOAc (3×30 mL) and CH2Cl2 (2×50 mL), the organic layers were

washed with brine, combined, dried over MgSO4 and filtered. Concentration under reduced

pressure and purification via chromatography (2→10% MeOH–CH2Cl2) yielded N4-

demethylalstonerine 190 (17.6 mg, 83%) as a pale yellow oil; Rf 0.3 (3% MeOH–CH2Cl2); FTIR

(film) max: 2923, 1704, 1651, 1617, 1470 cm-1

; m/z (CI) 323 [M+H]+ (Found [M+H]

+,

3323.1774. C20H22N2O2 requires [M+H]+, 323.1760);

Experimental

193

δH (400 MHz, CDCl3) 7.54 (1H, s, 21), 7.47 (1H, d, J 8.0 Hz, 9), 7.31 (1H, d, J 8.0 Hz, 12), 7.21

(1H, t, J 7.5 Hz, 11), 7.09 (1H, t, J 7.5 Hz, 10), 4.45 (1H, t, J 11.5 Hz, 17a),

4.36––4.24 (2H, m, 17b and 5), 3.64 (3H, s, N1Me), 3.50 (1H, d, J 7.0 Hz, 6a),

3.27 (1H, dd, J 16.5, 7.0 Hz, 6b), 3.11 (1H, br. s, N4H), 2.77––2.66 (1H, m, 15),

2.16––2.04 (4H, s, 18 and 14a), 1.92 (1H, dt, J 12.0, 4.5 Hz, 16), 1.81 (1H, td, J 12.0, 4.5 Hz,

14b);

δC (100 MHz, CDCl3) 195.4 (C19), 157.5 (C21), 136.9 (C13), 136.7 (C2), 126.8 (C8),

121.3 (C20), 121.1 (C11), 118.7 (C10), 117.8 (C9), 109.0 (C12), 107.1 (C7), 67.5 (C17), 48.3

(C3), 46.5 (C5), 37.4 (C16), 31.6 (C14), 29.0 (N1Me), 28.9 (C6), 25.0 (C18),

23.6 (C15). Data is in accordance with that previously reported by T. Kam et al.101

(±)-Alstonerine (4)

To a solution of N4-demethylalstonerine 190 (13.0 mg, 0.040 mmol, 1.0 equiv.) in THF

(1 mL) at –78°C was added Hünig’s Base (0.02 mL, 0.120 mmol, 3.0 equiv.) and iodomethane

(0.005mL, 0.080 mmol, 2.0 equiv.) and the solution allowed to warm slowly to rt overnight. To

the resulting cloudy solution was added saturated aqueous NaHCO3 (3 mL) and the aqueous

phase extracted with CH2Cl2 (4×20 mL) and EtOAc (3×20 mL). The combined organic layers

were dried over MgSO4 and filtered. Concentration under reduced pressure and chromatography

(50→75% EtOAc–hexane) yielded (±)-alstonerine 4 as a pale yellow oil (12.2 mg, 91%). Rf 0.3

(100% EtOAc); FTIR (film) max: 1652, 1618 cm–1

; m/z (CI) 337 [M+H]+ (Found [M+H]

+,

337.1908. C21H24N2O2 requires [M+H]+, 337.1916);

δH (400 MHz, CDCl3) 7.53 (1H, s, 21), 7.48 (1H, d, J 8.0 Hz, 9), 7.32 (1H, d, J 8.0 Hz, 12), 7.20

(1H, t, J 7.5 Hz, 11), 7.09 (1H, t, J 7.5 Hz, 10), 4.41 (1H, t, J 11.0 Hz, 17a),

4.17 (1H, ddd, J 11.0, 4.0, 1.5 Hz, 17b), 3.89 (1H, br. t, J 3.5 Hz, 3), 3.65 (3H, s, N1Me),

Experimental

194

3.33 (1H, dd, J 16.5, 7.0 Hz, 6a), 3.10 (1H, d, J 7.0 Hz, 5), 2.66––2.58 (1H, m, 15),

2.51 (1H, d, J 16.5 Hz, 6b), 2.33 (3H, br. s, N4Me), 2.15 (1H, dd, J 5.0, 3.0 Hz, 14a),

2.13––2.01 (4H, m, 14b then 18), 1.91 (1H, dt, J 12.0, 4.5 Hz, 16), 1.81 (1H, td, J 12.0, 4.5 Hz,

14);

δC (100 MHz, CDCl3) 195.5 (C19), 157.5 (C21), 137.1 (C13) 133.1 (C2), 126.6 (C8), 121.1

(C10), 120.8 (C20), 118.7 (C11), 117.9 (C9), 109.0 (C12), 105.9 (C7), 67.8 (C17), 54.7 (C3),

53.8 (C5), 41. 8 (C16), 38.5 (C14), 32.4 (C15), 29.1 (N1Me), 25.1 (N4Me), 22.9 (C18), 22.8

(C6). Data is in accordance with that previously reported.3,101

(4aR*,8S*,8aR*)-8-((1-Methylindol-3-yl)methyl)-7-tosyl-4-vinylidenetetrahydro-1H-


To a solution of lactam–lactone 91 (34.0 mg, 0.067 mmol, 1.0 equiv.) and PhNTf2 (26.0 mg,

0.074 mmol, 1.1 equiv.) in DMF (1 mL) at rt was added Hünig’s base (0.35 mL, 0.200 mmol,

3.0 equiv.) and the reaction mixture stirred for 30 min at rt. Saturated aqueous NH4Cl (2 mL)

was added and the aqueous layer extracted with CH2Cl2 (3×30 mL). The organic layers were

washed with brine and water, combined, dried over MgSO4 and filtered. Concentration under

reduced pressure and chromatography (25→50% EtOAc–hexane) yielded (4aR*,8S*,8aR*)-8-

((1-methylindol-3-yl)methyl)-7-tosyl-4-vinylidenetetrahydro-1H-pyrano[3,4-c]pyridine-

3,6(4H,7H)-dione 165 (19.2 mg, 88%) as an amorphous solid; Rf 0.33 (50% EtOAc–hexane);

FTIR (film) max: 1700, 1345, 1164 cm–1

; m/z (ES) 491 [M+H]+, 513 [M+Na]

+, (Found

[M+Na]+, 513.1465. C27H26N2O5S requires [M+Na]

+, 513.1460).

δH (400 MHz, CDCl3) 7.88 (2H, d, J 8.0 Hz, ortho-Ts), 7.69 (1H, d, J 8.0 Hz, ArH), 7.38––7.30

(3H, m, ArH and meta-Ts), 7.28 (1H, t, J 7.5 Hz, ArH), 7.18 (1H, t, J 7.5 Hz, ArH), 7.07 (1H, s,

2), 5.12 (1H, dd, J 15.5, 4.5 Hz, 18a), 4.95 (1H, dt, J 8.0, 4.0 Hz, 5), 4.63 (1H, dd, J 15.5, 4.5

Experimental

195

Hz, 18b), 4.24 (1H, dd, J 12.0, 3.5 Hz, 17a), 4.11 (1H, dd, J 12.0, 6.0 Hz, 17b), 3.80 (3H, s,

N1Me), 3.48 (1H, dd, J 14.5, 3.5 Hz, 6a), 3.23 (1H, dd, J 14.5, 8.5 Hz, 6b), 3.10 (1H, h, J 5.0 Hz,

15), 2.51 (1H, tq, J 9.5, 5.5, 4.5 Hz, 16), 2.43 (3H, s, TsMe), 2.38 (1H, dd, J 17.5, 5.0 Hz, 14a),

2.16 (1H, dd, J 17.5, 5.5 Hz, 14b).


135.4 (ipso-Ts), 129.4 (meta-Ts), 127.9 (ortho-Ts), 122.2 (C11), 119.8 (C10), 118.5 (C12),

109.7 (C9), 107.6 (C7), 96.5 (C20), 82.2 (C18), 69.3 (C17), 56.9 (C5), 36.7 (C14), 33.8 (C16),

32.9 (N1Me), 32.6 (C6), 30.6 (C15), 21.7 (TsMe).

3.1.13 Procedures from extension of methodology (Section 2.2.13)

N-((S*)-2-(4-Methoxyphenyl)-1-((3S*,4R*)-6-oxo-4-(phenylsulfonyl)tetrahydro-2H-pyran-

3-yl)ethyl)-4-methylbenzenesulfonamide (178a) and N-((S*)-2-(4-Methoxyphenyl)-1-

((3S*,4S*)-6-oxo-4-(phenylsulfonyl)tetrahydro-2H-pyran-3-yl)ethyl)-4-

methylbenzenesulfonamide (178b)

To a solution of trimethyl 3-(phenylsulfonyl)orthopropionate 88 (305 mg, 1.11 mmol, 2.0 equiv.)


and the solution stirred for 1 h at –78°C.


solution of hydroxymethyl-aziridine 178 (193 mg, 0.556 mmol, 1.0 equiv.) in THF (1 mL) at –

78°C and the solution stirred at –78°C for 1 h.

The dark red solution of deprotonated 88 was added dropwise via cannula to the solution of O-

lithio hydroxymethyl-aziridine 178, maintaining both solutions at –78°C throughout the addition.

The reaction mixture was allowed to warm slowly from –78°C to rt overnight.

Experimental

196

Aqueous HCl (2 M; 6.0 mL, 12.0 mmol, ~20 equiv.) was added and the solution stirred for 2 h at

rt. The aqueous layer was extracted with EtOAc (3×30 mL) and CH2Cl2 (2×50 mL). The

combined organic layers were washed with brine, dried over MgSO4 and filtered. Concentration

under reduced pressure and chromatography (33% EtOAc–hexane) yielded lactones 178 (120.7

mg, 82%) as a 2:1 mixture of sulfone epimers.

N-((S*)-2-(4-Methoxyphenyl)-1-((3S*,4R*)-6-oxo-4-(phenylsulfonyl)tetrahydro-2H-pyran-

3-yl)ethyl)-4-methylbenzenesulfonamide (178a)

Rf 0.50 (50% EtOAc–hexane); FTIR (film) max: 3266, 2942, 1751, 1611, 1514, 1446 cm–1

; m/z

(CI) 544 [M+H]+ (Found [M+H]

+, 544.1447. C27H29NO7S2 requires [M+H]

+, 544.1464).

δH (400 MHz, CDCl3) 7.80 (2H, app. d, J 8.0 Hz, ortho-PhSO2), 7.71––7.64 (3H, m, ortho-Ts

and para-PhSO2), 7.54 (2H, t, J 8.0 Hz, meta-PhSO2), 7.23 (2H, d, J 8.0 Hz, meta-Ts), 6.69 (4H,

ap. q, J 9.0 Hz, ortho- and meta-PMB), 5.82 (1H, d, J 9.5 Hz, 2), 4.42 (1H, dd, J 12.0, 6.0 Hz,

7a), 4.32 (1H, dd, J 12.0, 4.5 Hz, 7b), 4.25 (1H, q, J 13.0 Hz, 4), 3.75 (3H, s, OMe), 3.69––3.61

(1H, m, 2), 2.81 (2H, dd, J 7.0, 1.5 Hz, 5a and 5b), 2.58––2.47 (2H, m, 8a then 3), 2.39 (3H, s,

TsMe), 2.30 (1H, dd, J 14.0, 6.0 Hz, 8b);

δC (400 MHz, CDCl3) 169.9 (C6), 158.6 (para-PMB), 143.9 (para-Ts), 136.6 (ipso-Ts), 136.2

(ipso-PhSO2),134.3 (para-PhSO2), 129.9 (meta-Ts), 129.7 (meta-PMB), 129.6 (meta-PhSO2),

129.1 (ortho-PhSO2), 127.7 (ipso-PMB), 127.2 (ortho-Ts), 114.3 (ortho-PMB), 64.9 (C7), 57.3

(C2), 56.9 (C4), 55.2 (OMe), 37.6 (C8), 34.7 (C3), 28.8 (C5), 21.6 (TsMe).

Experimental

197

N-((S*)-2-(4-Methoxyphenyl)-1-((3S*,4S*)-6-oxo-4-(phenylsulfonyl)tetrahydro-2H-pyran-

3-yl)ethyl)-4-methylbenzenesulfonamide (178b)


; m/z

(CI) 544 [M+H]+ (Found [M+H]


+, 544.1464);

δH (400 MHz, CDCl3) 7.87 (2H, app. d J 8.0 Hz, ortho-PhSO2), 7.20 (1H, td, J 8.0, 1.0 Hz, para-

PhSO2), 7.64––7.55 (4H, m, ortho-Ts and meta-PhSO2), 7.20 (2H, d, J 8.0 Hz, meta-Ts), 6.91

(2H, d, J 8.0 Hz, meta-PMB), 6.68 (2H, d, J 8.0 Hz, ortho-PMB), 4.85 (1H, d, J 9.5 Hz, 2), 4.75

(1H, dd, J 12.0, 6.0 Hz, 7a), 4.58––4.44 (1H, m, 7b), 3.75 (4H, s, OMe and 4), 3.69––3.64 (1H,

m, 2), 3.00 (1H, dd, J 7.0, 1.5 Hz, 5a), 2.89––2.74 (2H, m, 8a then 5b), 2.60––2.50 (2H, m, 3

and 8b), 2.43 (3H, s, TsMe);

δC (400 MHz, CDCl3) 166.6 (C6), 158.8 (para-PMB), 143.5 (para-Ts), 137.7 (ipso-Ts), 137.1

(ipso-PhSO2),134.7 (para-PhSO2), 130.5 (meta-Ts), 130.0 (meta-PMB), 129.8 (meta-PhSO2),

129.7 (ortho-PhSO2), 128.6 (ipso-PMB), 127.2 (ortho-Ts), 114.3 (ortho-PMB), 69.1 (C7), 58.0

(C2), 55.2 (C4), 53.1 (OMe), 39.9 (C8), 38.1 (C3), 31.5 (C5), 21.6 (TsMe).

(5S*,6S*)-5-(Hydroxymethyl)-6-(4-methoxybenzyl)-1-tosyl-5,6-dihydropyridin-2(1H)-one

(177)

To a solution of lactones 178 (10.0 mg, 0.018 mmol, 1.0 equiv.) in toluene

(1 mL) was added trimethylaluminium (2 M in hexanes; 0.025 mL, 0.050 mmol, 2.8 equiv.) in a

Experimental

198

sealed tube and the reaction mixture stirred at rt for 1 h, then heated to 50°C for 5 min in the

microwave.

On cooling to rt, saturated aqueous Rochelle salt (5 mL) and EtOAc (10 mL) were added and the

resulting suspension stirred vigorously at rt overnight. Saturated aqueous NaHCO3

(5 mL) was added and the aqueous layer extracted with EtOAc (3×20 mL) and CH2Cl2

(2×30 mL). The combined organics were washed with brine, dried over MgSO4 and filtered.


(5S*,6S*)-5-(hydroxymethyl)-6-(4-methoxybenzyl)-1-tosyl-5,6-dihydropyridin-2(1H)-one 177

(6.91 mg, 96%) as a colourless amorphous solid; Rf 0.35 (50% EtOAc–hexane); FTIR (film)

max: 3530, 3056, 2917, 1687 3420, 2890, 1630, 1470 cm–1

; m/z (CI) 424 [M+Na]+ (Found

[M+Na]+, 424.1198. C21H23NO5S requires [M+Na]

+, 424.1195);


meta-Ts), 7.18 (2H, app. d, J 8.0 Hz, meta-PMB), 6.82 (2H, app. d, J 8.0 Hz, ortho-PMB), 6.49

(1H, dt, J 10.0, 2.0 Hz, 4), 5.91 (1H, dd, J 10.0, 3.0 Hz, 3), 5.29––5.25 (1H, m, 6), 3.80 (3H, s,

OMe), 3.67––3.62 (2H, m, 7a and 7b), 3.27––3.21 (1H, m, 5), 3.00 (1H, dd, J 14.0, 8.0 Hz, 8a),

2.91 (1H, dd, J 14.0, 8.0 Hz, 8b), 2.40 (3H, s, TsMe);

δC (125 MHz, CDCl3) 162.5 (C2), 158.9 (para-PMB), 144.5 (para-Ts), 143.2 (C4), 136.5

(ipso-Ts), 130.4 (meta-PMB), 129.2 (meta-Ts), 128.9 (ortho-Ts), 124.9 (ipso-PMB), 114.4

(meta-PMB), 61.5 (C7), 58.5 (C6), 55.2 (OMe), 43.6 (C5), 35.3 (C8), 21.6 (TsMe).

(S)-Methyl 7-methyl-5-(4-methylphenylsulfonamido)-3-(phenylsulfonyl)octanoate (173)

To a solution of trimethyl 3-(phenylsulfonyl)orthopropionate 88 (305 mg, 1.11 mmol, 2.0 equiv.)


Experimental

199

and the solution stirred for 1 h at –78°C. A solution of (S)-2-isobutyl-1-tosylaziridine 172 was

added and the solution allowed to warm slowly from –78°C to rt overnight.

Aqueous HCl (2 M; 6.0 mL, 12.0 mmol, ~20 equiv.) was added and the solution stirred for 2 h at



under reduced pressure and chromatography (33% EtOAc–hexane) yielded (S)-methyl 7-methyl-

5-(4-methylphenylsulfonamido)-3-(phenylsulfonyl)octanoate 173 (121 mg, 82%) as a colourless

oil and a 7:3 mixture of sulfone epimers; Rf 0.50 (50% EtOAc–hexane); [α]D – 6.6 (c 0.73,

CH2Cl2); FTIR (film) max: 3279, 2955, 1738, 1598, 1447, 1305, 1156 cm–1

; m/z (ES) 482

[M+H]+ (Found [M+H]


+, 482.1671).

δH (400 MHz, CDCl3) 7.95 (2H, d, J 8.0 Hz, ortho-Ts), 7.31 (2H, d, J 8.0 Hz, meta-Ts), 6.63

(3H, br. t, J 8.0 Hz, ArH), 5.86 (2H, dd, J 10.0, 3.0 Hz, ArH), 4.88 (1H, dt, J 10.5, 5.0 Hz, 6),

2.73 (1H, ddt, J 18.5, 6.0, 2.5 Hz, 5), 2.50––2.38 (4H, m, TsMe), 1.72 (1H, ddd, J 14.0, 10.0, 4.5

Hz, 5a), 1.65––1.44 (3H, m, 5b, 4a and 4b), 1.00 (3H, d, J 6.5 Hz, iPr), 0.94 (3H, d, J 6.5 Hz,

iPr);

δC (100 MHz, CDCl3) 172.2 (CO), 141.7 (para-Ts), 129.2 (meta-Ts), 129.0 (ortho-Ts), 124.9

(ipso-Ts), 53.6 (C6), 42.0 (C7), 28.4 (C5), 25.4 (C8), 23.4 (iPrMe), 21.7 (TsMe), 21.4 (iPrMe).

(S)-6-Isobutyl-1-tosyl-5,6-dihydropyridin-2(1H)-one (171)

To a stirred solution (S)-methyl 7-methyl-5-(4-methylphenylsulfonamido)-3-

(phenylsulfonyl)octanoate 173 (305 mg, 1.11 mmol, 2.0 equiv.) in toluene (1 mL) at

–78°C was added trimethylaluminium (2.0 M in toluene; 0.67 mL, 1.67 mmol, 2.5 equiv.) and

Experimental

200

the solution allowed to warm slowly from –78°C to rt overnight. The reaction mixture was then

heated under reflux at 120°C for 1 h and cooled to rt.

Saturated aqueous Rochelle salt (2 mL) and EtOAc (5 mL) were added and the solution stirred

vigorously for 2 h at rt. The aqueous layer was extracted with EtOAc (3×30 mL) and CH2Cl2

(2×50 mL). The combined organic layers were washed with brine, dried over MgSO4 and

filtered. Concentration under reduced pressure and chromatography (33% EtOAc–hexane)

yielded (S)-6-isobutyl-1-tosyl-5,6-dihydropyridin-2(1H)-one 171 (121 mg, 82%) as a colourless

oil; Rf 0.50 (50% EtOAc–hexane); [α]D – 17.0 (c 0.47, CH2Cl2); FTIR (film) max: 2956, 1736,

1686, 1597, 1384, 1345, 1167 cm–1

; m/z (ES) 308 [M+H]+ (Found [M+H]

+, 3081344.

C16H21NO3S requires [M+H]+, 308.1320).


(1H, br. t, J 8.0 Hz, 4), 5.86 (1H, dd, J 10.0, 3.0 Hz, 3), 4.88 (1H, dt, J 10.5, 5.0 Hz, 6), 2.73 (1H,

ddt, J 18.5, 6.0, 2.5 Hz, 5), 2.50––2.38 (4H, m, TsMe and 7), 1.72 (1H, ddd, J 14.0, 10.0, 4.5 Hz,

8), 1.65––1.44 (3H, m, iPr), 1.00 (3H, d, J 6.5 Hz, iPr), 0.94 (3H, d, J 6.5 Hz, iPr);

δC (100 MHz, CDCl3) 141.7 (para-Ts), 129.2 (meta-Ts), 129.0 (ortho-Ts), 124.9 (ipso-Ts), 53.6

(C6), 42.0 (C7), 28.4 (C5), 25.4 (C8), 23.4 (iPrMe), 21.7 (TsMe), 21.4 (iPrMe).

(S,E)-Methyl 7-methyl-5-(4-methylphenylsulfonamido)oct-2-enoate (175)

Rf 0.50 (50% EtOAc–hexane); FTIR (film) max: 3280, 1723, 1708, 1658, 1599, 1327, 1159 cm–

1; m/z (ES) 340 [M+H]

+ (Found [M+H]

+, 340.1584. C16H21NO3S requires [M+H]

+, 340.1583).


(1H, dt, J 15.5, 7.5 Hz, 4), 5.76 (1H, dt, J 15.5, 1.5 Hz, 5), 4.30 (1H, d, J 8.5 Hz, NHTs), 3.75

(3H, s, OMe), 3.46 (1H, tq, J 8.5, 5.5 Hz, ), 2.46 (3H, s, TsMe), 2.34 (2H, dddd, J 15.0, 12.5,

Experimental

201

9.0, 7.0 Hz, 3), 1.73––1.44 (2H, m, 7a and 7b), 1.38––1.09 (2H, m, 7), 0.83 (3H, d, J 6.5 Hz,

Me), 0.70 (3H, d, J 6.5 Hz, Me).

δC (100 MHz, CDCl3) 143.6 (para-Ts), 137.8 (beta C=C), 129.8 (meta-Ts), 127.1 (ortho-Ts),

124.5 (ipso-Ts), 51.6 (OMe), 51.0 (C2), 44.0 (C7), 38.2 (C3), 24.4 (C8), 22.8 (iPrMe), 21.7

(iPrMe), 21.6 (TsMe).

(4R*,6S*)-6-Isobutyl-4-(phenylsulfonyl)-1-tosylpiperidin-2-one (174)

Rf 0.50 (50% EtOAc–hexane); FTIR (film) max: 2957, 1739, 1693, 1596, 1447, 1348, 1166 cm–

1; m/z (ES) 450 [M+H]

+ (Found [M+H]


+, 450.1409).

δH (400 MHz, CDCl3) 7.95––7.80 (4H, m, ArH), 7.79––7.65 (1H, m, ArH), 7.59 (2H, td, J 7.5,

4.0 Hz, ArH), 7.30 (2H, d, J 8.0 Hz, ArH), 4.78 (1H, ddq, J 10.0, 5.0, 3.0 Hz, 4), 3.56––3.29

(1H, m, 6), 2.84––2.70 (1H, m, 3a), 2.68––2.52 (2H, m, 3b), 2.51––2.36 (5H, m, 5a, 7b and

TsMe), 1.95 (1H, td, J 13.5, 4.5 Hz, 5b), 1.76 (1H, dtd, J 12.5, 9.0, 8.5, 4.5 Hz, 7a), 1.71––1.50

(2H, m,), 1.44 (1H, ddd, J 14.5, 10.5, 4.5 Hz, 8). 1.04––0.91 (6H, m iPr);

δC (100 MHz, CDCl3) 166.0, 145.2, 135.9, 134.6, 129.7, 129.5, 129.4, 129.3, 129.1, 129.0,

128.7, 56.0, 54.3, 53.6, 53.4, 46.2, 43.5, 33.6, 32.8, 25.3, 25.1, 23.6, 21.7, 20.9.

Experimental

202

(3R*,4R*,5S*)-Methyl 6-(tert-butyldimethylsilyloxy)-5-(4-methylphenylsulfonamido)-4-

phenyl-3-(phenylsulfonyl)hexanoate (183a) and (3S*,4R*,5S*)-Methyl 6-hydroxy-5-(4-

methylphenylsulfonamido)-4-phenyl-3-(phenylsulfonyl)hexanoate (183b)

To a solution of trimethyl 3-(phenylsulfonyl)orthopropionate 88 (150 mg, 0.456 mmol, 2.0

equiv.) in THF (5 mL) at –78°C was added n-BuLi (2.48 M in hexanes; 0.28 mL, 0.684 mmol,

1.5 equiv.) and the solution stirred for 1 h at –78°C.


solution of hydroxymethyl-aziridine 180 (70.0 mg, 0.228 mmol, 1.0 equiv.) in THF (1 mL) at –

78°C and the solution stirred at –78°C for 1 h.

The dark red solution of deprotonated 88 was added dropwise via cannula to the solution of O-

lithio hydroxymethyl-aziridine 180, maintaining both solutions at –78°C throughout the addition.

The reaction mixture was allowed to warm slowly from –78°C to rt overnight.

Aqueous HCl (2 M; 4.0 mL, 8.0 mmol, ~10 equiv.) was added and the solution stirred for 2h at



under reduced pressure and chromatography (33% EtOAc–hexane) yielded a complex mixture

that included (3R*,4R*,5S*)-methyl 6-(tert-butyldimethylsilyloxy)-5-(4-

methylphenylsulfonamido)-4-phenyl-3-(phenylsulfonyl)hexanoate 183a and (3S*,4R*,5S*)-

methyl 6-hydroxy-5-(4-methylphenylsulfonamido)-4-phenyl-3-(phenylsulfonyl)hexanoate 183b.

Experimental

203

(3R*,4R*,5S*)-Methyl 6-(tert-butyldimethylsilyloxy)-5-(4-methylphenylsulfonamido)-4-

phenyl-3-(phenylsulfonyl)hexanoate (183a)


; m/z

(ES) 532 [M+H]+ (Found [M+H]


+, 532.1464).

δH (400 MHz, CDCl3) 8.00––7.94 (2H, m, ortho-PhSO2), 7.82––7.77 (2H, m, ortho-Ts), 7.69––

7.63 (1H, m, para-PhSO2), 7.60––7.54 (2H, m, meta-PhSO2), 7.31 (2H, d, J 8.0 Hz, meta-Ts),

7.28––7.24 (2H, m, ortho-Ph), 7.18––7.12 (2H, m, meta-Ph), 4.83 (1H, d, J 9.0 Hz, N4H),

4.59––4.36 (2H, m, 4 and 6), 3.81 (1H, dd, J 8.0, 4.5 Hz, 5), 3.52––3.42 (1H, m, 7a), 3.31 (3H, s,

OMe), 3.28––3.17 (1H, dd, J 11.5, 5.5 Hz, 7b), 2.52––2.41 (4H, m, 3a and TsMe), 2.30––2.18

(1H, dd, J 18.0, 5.5 Hz, 3b);

δC (100 MHz, CDCl3) 170.4 (C2), 143.7 (para-Ts), 137.7 (ipso-PhSO2), 137.1 (ipso-Ts), 135.3

(ipso-Ph), 134.1 (para-PhSO2), 130.3 (Ph), 129.8 (ortho-Ph), 129.3 (meta-Ts), 129.2 (meta-

PhSO2), 128.9 (ortho-PhSO2), 128.2 (Ph), 127.5 (ortho-Ts), 63.1 (C7), 59.9 (C4), 56.2 (C6),

52.0 (OMe), 44.7 (C5), 33.3 (C3), 21.6 (TsMe).

Experimental

204

(3S*,4R*,5S*)-Methyl 6-hydroxy-5-(4-methylphenylsulfonamido)-4-phenyl-3-

(phenylsulfonyl)hexanoate (183b)


; m/z

(ES) 532 [M+H]+ (Found [M+H]


+, 532.1464).

δH (400 MHz, CDCl3) 7.67––7.62 (2H, m, ortho-Ts), 7.56––7.49 (3H, m, ortho- and para-

PhSO2), 7.41––7.34 (2H, m, meta-PhSO2), 7.32––7.25 (2H, s, meta-Ts), 7.23––7.15 (1H, m,

para-Ph), 7.11––7.02 (4H, m, ortho- and meta-Ph), 4.44––4.33 (1H, m, 4), 4.21––4.10 (1H, m,

5), 3.75 (3H, s, OMe), 3.69––3.60 (1H, m, 6), 3.60––3.50 (1H, m, 7a), 3.41––3.30 (1H, q, J 6.0

Hz, 7b), 3.13 (1H, dd, J 17.5, 5.0 Hz, 3a), 2.99 (1H, dd, J 17.5, 7.5 Hz, 3b), 2.45 (3H, s, TsMe);

δC (100 MHz, CDCl3) 171.1 (C2), 143.9 (para-Ts), 139.8 (para-PhSO2), 137.1 (ipso-Ts), 134.9

(ipso-Ph), 133.2 (ipso-PhSO2), 129.9 (meta-Ts), 129.8 (ortho-Ph), 129.0 (meta-Ph), 128.7

(meta-PhSO2), 128.1 (para-Ph), 127.9 (ortho-PhSO2), 127.1 (ortho-Ts), 62.9 (C4), 62.8 (C7),

55.3 (C5), 52.4 (OMe), 45.7 (C6), 31.1 (C3), 21.6 (TsMe).

Appendix

205

Chapter 4

Appendix

Appendix

206

4.1 X-Ray Crystallography data

4.1.1 4-Methyl-N-((S)-2-(1-methyl-1H-indol-3-yl)-1-((3R,4R)-6-oxo-4-

(phenylsulfonyl)tetrahydro-2H-pyran-3-yl)ethyl)benzenesulfonamide (109a)

Table 1. Crystal data and structure refinement for 109a.

Identification code DC1202

Formula C29 H30 N2 O6 S2

Formula weight 566.67

Temperature 173 K

Diffractometer, wavelength OD Xcalibur 3, 0.71073 Å

Appendix

207

Crystal system, space group Monoclinic, P2(1)/n

Unit cell dimensions a = 7.95229(13) Å = 90°

b = 16.6978(3) Å = 90.4896(17)°

c = 20.2810(4) Å = 90°

Volume, Z 2692.93(8) Å3, 4

Density (calculated) 1.398 Mg/m3

Absorption coefficient 0.245 mm-1

F(000) 1192

Crystal colour / morphology Colourless blocky needles

Crystal size 0.44 x 0.17 x 0.14 mm3

range for data collection 3.00 to 29.56°

Index ranges -10<=h<=10, -22<=k<=21, -26<=l<=22

Reflns collected / unique 22471 / 6598 [R(int) = 0.0253]

Reflns observed [F>4(F)] 5366

Absorption correction Analytical

Max. and min. transmission 0.970 and 0.929

Refinement method Full-matrix least-squares on F2

Data / restraints / parameters 6598 / 1 / 359

Goodness-of-fit on F2 1.051

Final R indices [F>4(F)] R1 = 0.0394, wR2 = 0.0933

R indices (all data) R1 = 0.0530, wR2 = 0.0998

Extinction coefficient 0.0015(4)

Largest diff. peak, hole 0.332, -0.379 eÅ-3

Appendix

208

Mean and maximum shift/error 0.000 and 0.001

Table 2. Bond lengths [Å] and angles [°] for DC1202.

N(1)-C(9) 1.375(2)

N(1)-C(2) 1.377(2)

N(1)-C(10) 1.457(2)

C(2)-C(3) 1.363(2)

C(3)-C(4) 1.436(2)

C(3)-C(11) 1.500(2)

C(4)-C(5) 1.398(2)

C(4)-C(9) 1.420(2)

C(5)-C(6) 1.388(2)

C(6)-C(7) 1.400(3)

C(7)-C(8) 1.380(3)

C(8)-C(9) 1.396(2)

C(11)-C(12) 1.535(2)

C(12)-N(19) 1.4627(18)

C(12)-C(13) 1.5596(18)

C(13)-C(14) 1.522(2)

C(13)-C(18) 1.547(2)

C(14)-O(15) 1.454(2)

O(15)-C(16) 1.346(2)

C(16)-O(16) 1.200(2)

C(16)-C(17) 1.504(2)

C(17)-C(18) 1.535(2)

C(18)-S(30) 1.7949(15)

N(19)-S(20) 1.6142(13)

S(20)-O(22) 1.4274(13)

S(20)-O(21) 1.4379(13)

S(20)-C(23) 1.7643(15)

C(23)-C(24) 1.382(2)

Appendix

209

C(23)-C(28) 1.392(2)

C(24)-C(25) 1.388(2)

C(25)-C(26) 1.381(2)

C(26)-C(27) 1.386(2)

C(26)-C(29) 1.513(2)

C(27)-C(28) 1.384(2)

S(30)-O(32) 1.4394(12)

S(30)-O(31) 1.4401(11)

S(30)-C(33) 1.7651(16)

C(33)-C(38) 1.387(2)

C(33)-C(34) 1.393(2)

C(34)-C(35) 1.383(2)

C(35)-C(36) 1.387(3)

C(36)-C(37) 1.377(3)

C(37)-C(38) 1.387(2)

C(9)-N(1)-C(2) 108.41(13)

C(9)-N(1)-C(10) 126.23(14)

C(2)-N(1)-C(10) 125.31(15)

C(3)-C(2)-N(1) 110.71(14)

C(2)-C(3)-C(4) 106.35(13)

C(2)-C(3)-C(11) 126.16(15)

C(4)-C(3)-C(11) 127.45(14)

C(5)-C(4)-C(9) 118.35(15)

C(5)-C(4)-C(3) 134.75(14)

C(9)-C(4)-C(3) 106.89(13)

C(6)-C(5)-C(4) 119.38(15)

C(5)-C(6)-C(7) 120.96(16)

C(8)-C(7)-C(6) 121.35(16)

C(7)-C(8)-C(9) 117.52(15)

N(1)-C(9)-C(8) 129.91(14)

Appendix

210

N(1)-C(9)-C(4) 107.64(13)

C(8)-C(9)-C(4) 122.43(15)

C(3)-C(11)-C(12) 114.92(12)

N(19)-C(12)-C(11) 110.35(12)

N(19)-C(12)-C(13) 110.19(11)

C(11)-C(12)-C(13) 110.04(11)

C(14)-C(13)-C(18) 108.13(12)

C(14)-C(13)-C(12) 111.89(12)

C(18)-C(13)-C(12) 112.02(11)

O(15)-C(14)-C(13) 111.06(12)

C(16)-O(15)-C(14) 116.23(12)

O(16)-C(16)-O(15) 119.47(15)

O(16)-C(16)-C(17) 124.92(16)

O(15)-C(16)-C(17) 115.61(14)

C(16)-C(17)-C(18) 111.69(12)

C(17)-C(18)-C(13) 113.65(12)

C(17)-C(18)-S(30) 110.81(10)

C(13)-C(18)-S(30) 109.08(10)

C(12)-N(19)-S(20) 124.07(11)

O(22)-S(20)-O(21) 119.57(8)

O(22)-S(20)-N(19) 106.86(7)

O(21)-S(20)-N(19) 106.25(7)

O(22)-S(20)-C(23) 107.53(7)

O(21)-S(20)-C(23) 107.72(8)

N(19)-S(20)-C(23) 108.52(7)

C(24)-C(23)-C(28) 120.86(14)

C(24)-C(23)-S(20) 120.03(12)

C(28)-C(23)-S(20) 119.11(12)

C(23)-C(24)-C(25) 119.03(15)

C(26)-C(25)-C(24) 121.36(16)

Appendix

211

C(25)-C(26)-C(27) 118.47(15)

C(25)-C(26)-C(29) 120.88(17)

C(27)-C(26)-C(29) 120.65(17)

C(28)-C(27)-C(26) 121.62(16)

C(27)-C(28)-C(23) 118.64(15)

O(32)-S(30)-O(31) 118.50(8)

O(32)-S(30)-C(33) 107.88(7)

O(31)-S(30)-C(33) 109.01(7)

O(32)-S(30)-C(18) 106.90(7)

O(31)-S(30)-C(18) 109.14(7)

C(33)-S(30)-C(18) 104.51(7)

C(38)-C(33)-C(34) 121.60(15)

C(38)-C(33)-S(30) 119.25(12)

C(34)-C(33)-S(30) 119.07(12)

C(35)-C(34)-C(33) 118.72(16)

C(34)-C(35)-C(36) 120.13(16)

C(37)-C(36)-C(35) 120.49(17)

C(36)-C(37)-C(38) 120.50(17)

C(33)-C(38)-C(37) 118.51(15)

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212

4.1.2 4-methyl-N-((S)-2-(1-methyl-1H-indol-3-yl)-1-((3R,4S)-6-oxo-4-

(phenylsulfonyl)tetrahydro-2H-pyran-3-yl)ethyl)benzenesulfonamide (109b)

Table 1. Crystal data and structure refinement for 109b.


Formula C29 H30 N2 O6 S2


Temperature 173 K


Appendix

213

Crystal system, space group Triclinic, P-1

Unit cell dimensions a = 9.7991(3) Å = 71.755(4)°

b = 12.5139(6) Å = 73.837(3)°

c = 12.5365(4) Å = 70.745(4)°

Volume, Z 1351.79(10) Å3, 2



F(000) 596

Crystal colour / morphology Colourless needles



Index ranges -14<=h<=13, -17<=k<=17, -18<=l<=18












Appendix

214


N(1)-C(9) 1.370(2)

N(1)-C(2) 1.3753(18)

N(1)-C(10) 1.4533(19)

C(2)-C(3) 1.3681(19)

C(3)-C(4) 1.4375(19)

C(3)-C(11) 1.4969(17)

C(4)-C(5) 1.399(2)

C(4)-C(9) 1.4233(19)

C(5)-C(6) 1.390(2)

C(6)-C(7) 1.405(3)

C(7)-C(8) 1.361(3)

C(8)-C(9) 1.402(2)

C(11)-C(12) 1.5395(17)

C(12)-N(19) 1.4654(16)

C(12)-C(13) 1.5607(16)

C(13)-C(14) 1.5253(17)

C(13)-C(18) 1.5438(16)

C(14)-O(15) 1.4582(15)

O(15)-C(16) 1.3445(16)

C(16)-O(16) 1.2123(15)

C(16)-C(17) 1.5079(18)

C(17)-C(18) 1.5286(16)

C(18)-S(30) 1.8069(13)

N(19)-S(20) 1.6074(11)

S(20)-O(21) 1.4368(10)

S(20)-O(22) 1.4403(10)

S(20)-C(23) 1.7662(12)

C(23)-C(24) 1.3844(19)

Appendix

215

C(23)-C(28) 1.3921(18)

C(24)-C(25) 1.3911(19)

C(25)-C(26) 1.387(2)

C(26)-C(27) 1.390(2)

C(26)-C(29) 1.5068(19)

C(27)-C(28) 1.3853(18)

S(30)-O(31) 1.4398(10)

S(30)-O(32) 1.4403(10)

S(30)-C(33) 1.7657(13)

C(33)-C(34) 1.384(2)

C(33)-C(38) 1.387(2)

C(34)-C(35) 1.399(2)

C(35)-C(36) 1.376(3)

C(36)-C(37) 1.376(3)

C(37)-C(38) 1.387(2)

C(9)-N(1)-C(2) 108.75(11)

C(9)-N(1)-C(10) 125.86(14)

C(2)-N(1)-C(10) 125.37(14)

C(3)-C(2)-N(1) 110.30(13)

C(2)-C(3)-C(4) 106.64(12)

C(2)-C(3)-C(11) 126.93(13)

C(4)-C(3)-C(11) 126.43(12)

C(5)-C(4)-C(9) 119.32(13)

C(5)-C(4)-C(3) 134.30(13)

C(9)-C(4)-C(3) 106.37(12)

C(6)-C(5)-C(4) 118.49(15)

C(5)-C(6)-C(7) 120.98(16)

C(8)-C(7)-C(6) 121.93(15)

C(7)-C(8)-C(9) 117.79(15)

Appendix

216

N(1)-C(9)-C(8) 130.59(14)

N(1)-C(9)-C(4) 107.93(12)

C(8)-C(9)-C(4) 121.49(15)

C(3)-C(11)-C(12) 112.96(10)

N(19)-C(12)-C(11) 109.87(10)

N(19)-C(12)-C(13) 108.53(9)

C(11)-C(12)-C(13) 113.05(9)

C(14)-C(13)-C(18) 109.13(10)

C(14)-C(13)-C(12) 115.45(10)

C(18)-C(13)-C(12) 114.27(9)

O(15)-C(14)-C(13) 111.94(10)

C(16)-O(15)-C(14) 123.17(10)

O(16)-C(16)-O(15) 117.51(12)

O(16)-C(16)-C(17) 121.59(12)

O(15)-C(16)-C(17) 120.69(11)

C(16)-C(17)-C(18) 115.44(10)

C(17)-C(18)-C(13) 107.96(9)

C(17)-C(18)-S(30) 109.13(9)

C(13)-C(18)-S(30) 113.13(8)

C(12)-N(19)-S(20) 124.57(9)

O(21)-S(20)-O(22) 119.42(6)

O(21)-S(20)-N(19) 108.67(6)

O(22)-S(20)-N(19) 105.31(6)

O(21)-S(20)-C(23) 106.09(6)

O(22)-S(20)-C(23) 107.22(6)

N(19)-S(20)-C(23) 109.96(6)

C(24)-C(23)-C(28) 120.36(12)

C(24)-C(23)-S(20) 119.71(10)

C(28)-C(23)-S(20) 119.60(10)

C(23)-C(24)-C(25) 119.22(13)

Appendix

217

C(26)-C(25)-C(24) 121.44(13)

C(25)-C(26)-C(27) 118.28(13)

C(25)-C(26)-C(29) 120.54(14)

C(27)-C(26)-C(29) 121.18(14)

C(28)-C(27)-C(26) 121.30(13)

C(27)-C(28)-C(23) 119.38(12)

O(31)-S(30)-O(32) 118.90(7)

O(31)-S(30)-C(33) 109.37(6)

O(32)-S(30)-C(33) 108.32(7)

O(31)-S(30)-C(18) 108.42(6)

O(32)-S(30)-C(18) 107.82(6)

C(33)-S(30)-C(18) 102.81(6)

C(34)-C(33)-C(38) 121.76(13)

C(34)-C(33)-S(30) 119.81(11)

C(38)-C(33)-S(30) 118.42(11)

C(33)-C(34)-C(35) 118.34(16)

C(36)-C(35)-C(34) 120.28(17)

C(35)-C(36)-C(37) 120.51(15)

C(36)-C(37)-C(38) 120.46(17)

C(33)-C(38)-C(37) 118.62(16)

Appendix

218

4.1.3 4-Methyl-N-((S)-2-(1-methyl-1H-indol-3-yl)-1-((3R,4R)-6-oxo-4-

(phenylsulfonyl)tetrahydro-2H-pyran-3-yl)ethyl)benzenesulfonamide (118)

The unit cell was found to be composed of six independent (highly similar) conformers (shown

below)

Conformer 1:

Appendix

219

Conformer 2:

Appendix

220

Conformer 3:

Appendix

221

Conformer 4:

Conformer 5:

Conformer 6:

Appendix

222

Table 1. Crystal data and structure refinement for 118.


Formula C29 H30 N2 O6 S2, 0.54(H2 O)


Temperature 173 K




Appendix

223

b = 20.8685(14) Å = 77.711(6)°

c = 28.0277(19) Å = 77.023(6)°

Volume, Z 8353.8(11) Å3, 12



F(000) 3641

Crystal colour / morphology Colourless blocks



Index ranges -20<=h<=19, -27<=k<=27, -36<=l<=31













Appendix

224

N(1A)-C(2A) 1.364(8)

N(1A)-C(6A) 1.505(8)

N(1A)-S(7A) 1.694(6)

C(2A)-O(2A) 1.216(8)

C(2A)-C(3A) 1.514(9)

C(3A)-C(4A) 1.528(8)

C(4A)-C(5A) 1.558(9)

C(4A)-S(17A) 1.777(7)

C(5A)-C(26A) 1.515(8)

C(5A)-C(6A) 1.535(8)

C(6A)-C(28A) 1.540(8)

S(7A)-O(8A) 1.419(5)

S(7A)-O(9A) 1.430(5)

S(7A)-C(10A) 1.710(8)

C(10A)-C(15A) 1.382(10)

C(10A)-C(11A) 1.387(9)

C(11A)-C(12A) 1.387(10)

C(12A)-C(13A) 1.379(11)

C(13A)-C(14A) 1.379(10)

C(13A)-C(16A) 1.525(10)

C(14A)-C(15A) 1.409(9)

S(17A)-O(19A) 1.440(5)

S(17A)-O(18A) 1.442(5)

S(17A)-C(20A) 1.742(8)

C(20A)-C(21A) 1.384(10)

C(20A)-C(25A) 1.419(9)

C(21A)-C(22A) 1.398(11)

C(22A)-C(23A) 1.336(11)

C(23A)-C(24A) 1.371(11)

C(24A)-C(25A) 1.418(10)

Appendix

225

C(26A)-O(27A) 1.394(7)

C(28A)-C(29A) 1.466(9)

C(29A)-C(30A) 1.373(9)

C(29A)-C(37A) 1.443(9)

C(30A)-N(31A) 1.384(8)

N(31A)-C(32A) 1.368(9)

N(31A)-C(38A) 1.460(9)

C(32A)-C(33A) 1.387(9)

C(32A)-C(37A) 1.417(9)

C(33A)-C(34A) 1.428(11)

C(34A)-C(35A) 1.404(11)

C(35A)-C(36A) 1.374(10)

C(36A)-C(37A) 1.409(8)

N(1B)-C(2B) 1.398(8)

N(1B)-C(6B) 1.481(8)

N(1B)-S(7B) 1.676(6)

C(2B)-O(2B) 1.211(7)

C(2B)-C(3B) 1.527(8)

C(3B)-C(4B) 1.540(8)

C(4B)-C(5B) 1.533(8)

C(4B)-S(17B) 1.793(6)

C(5B)-C(6B) 1.545(8)

C(5B)-C(26B) 1.553(9)

C(6B)-C(28B) 1.546(8)

S(7B)-O(9B) 1.426(5)

S(7B)-O(8B) 1.446(5)

S(7B)-C(10B) 1.776(6)

C(10B)-C(15B) 1.366(9)

C(10B)-C(11B) 1.405(9)

C(11B)-C(12B) 1.353(10)

Appendix

226

C(12B)-C(13B) 1.385(11)

C(13B)-C(14B) 1.417(10)

C(13B)-C(16B) 1.510(9)

C(14B)-C(15B) 1.340(9)

S(17B)-O(19B) 1.436(5)

S(17B)-O(18B) 1.443(5)

S(17B)-C(20B) 1.756(7)

C(20B)-C(25B) 1.364(9)

C(20B)-C(21B) 1.389(10)

C(21B)-C(22B) 1.408(11)

C(22B)-C(23B) 1.368(10)

C(23B)-C(24B) 1.363(10)

C(24B)-C(25B) 1.363(10)

C(26B)-O(27B) 1.390(9)

C(28B)-C(29B) 1.516(9)

C(29B)-C(30B) 1.380(9)

C(29B)-C(37B) 1.392(9)

C(30B)-N(31B) 1.385(9)

N(31B)-C(32B) 1.383(9)

N(31B)-C(38B) 1.471(9)

C(32B)-C(33B) 1.395(10)

C(32B)-C(37B) 1.420(9)

C(33B)-C(34B) 1.367(10)

C(34B)-C(35B) 1.414(10)

C(35B)-C(36B) 1.393(10)

C(36B)-C(37B) 1.381(9)

N(1C)-C(2C) 1.347(9)

N(1C)-C(6C) 1.463(8)

N(1C)-S(7C) 1.682(6)

C(2C)-O(2C) 1.226(8)

Appendix

227

C(2C)-C(3C) 1.501(10)

C(3C)-C(4C) 1.546(9)

C(4C)-C(5C) 1.500(9)

C(4C)-S(17C) 1.820(8)

C(5C)-C(26C) 1.537(8)

C(5C)-C(6C) 1.542(9)

C(5C)-C(26I) 1.549(9)

C(6C)-C(28C) 1.522(8)

S(7C)-O(9C) 1.420(5)

S(7C)-O(8C) 1.450(5)

S(7C)-C(10C) 1.792(7)

C(10C)-C(15C) 1.370(10)

C(10C)-C(11C) 1.391(9)

C(11C)-C(12C) 1.396(10)

C(12C)-C(13C) 1.380(11)

C(13C)-C(14C) 1.348(10)

C(13C)-C(16C) 1.481(10)

C(14C)-C(15C) 1.378(10)

S(17C)-O(19C) 1.436(5)

S(17C)-O(18C) 1.437(5)

S(17C)-C(20C) 1.774(9)

C(20C)-C(25C) 1.372(9)

C(20C)-C(21C) 1.373(10)

C(21C)-C(22C) 1.380(11)

C(22C)-C(23C) 1.388(11)

C(23C)-C(24C) 1.376(12)

C(24C)-C(25C) 1.374(12)

C(26C)-O(27C) 1.401(9)

C(26I)-O(27I) 1.422(10)

C(28C)-C(29C) 1.490(9)

Appendix

228

C(29C)-C(30C) 1.378(9)

C(29C)-C(37C) 1.436(10)

C(30C)-N(31C) 1.369(8)

N(31C)-C(32C) 1.394(9)

N(31C)-C(38C) 1.460(8)

C(32C)-C(37C) 1.388(10)

C(32C)-C(33C) 1.416(10)

C(33C)-C(34C) 1.358(11)

C(34C)-C(35C) 1.395(11)

C(35C)-C(36C) 1.378(10)

C(36C)-C(37C) 1.385(10)

N(1D)-C(2D) 1.382(9)

N(1D)-C(6D) 1.510(8)

N(1D)-S(7D) 1.707(6)

C(2D)-O(2D) 1.270(9)

C(2D)-C(3D) 1.482(10)

C(3D)-C(4D) 1.548(9)

C(4D)-C(5D) 1.548(10)

C(4D)-S(17D) 1.792(8)

C(5D)-C(26D) 1.525(8)

C(5D)-C(26J) 1.533(9)

C(5D)-C(6D) 1.534(9)

C(6D)-C(28D) 1.527(8)

S(7D)-O(8D) 1.410(5)

S(7D)-O(9D) 1.421(5)

S(7D)-C(10D) 1.741(8)

C(10D)-C(15D) 1.376(10)

C(10D)-C(11D) 1.385(9)

C(11D)-C(12D) 1.403(10)

C(12D)-C(13D) 1.402(11)

Appendix

229

C(13D)-C(14D) 1.371(10)

C(13D)-C(16D) 1.497(10)

C(14D)-C(15D) 1.398(10)

S(17D)-O(19D) 1.435(5)

S(17D)-O(18D) 1.444(5)

S(17D)-C(20D) 1.785(8)

C(20D)-C(21D) 1.371(9)

C(20D)-C(25D) 1.404(9)

C(21D)-C(22D) 1.399(11)

C(22D)-C(23D) 1.372(10)

C(23D)-C(24D) 1.380(10)

C(24D)-C(25D) 1.357(10)

C(26D)-O(27D) 1.412(9)

C(26J)-O(27J) 1.407(9)

C(28D)-C(29D) 1.481(9)

C(29D)-C(30D) 1.375(9)

C(29D)-C(37D) 1.460(10)

C(30D)-N(31D) 1.367(9)

N(31D)-C(32D) 1.381(9)

N(31D)-C(38D) 1.453(9)

C(32D)-C(37D) 1.405(9)

C(32D)-C(33D) 1.427(10)

C(33D)-C(34D) 1.339(11)

C(34D)-C(35D) 1.398(11)

C(35D)-C(36D) 1.361(11)

C(36D)-C(37D) 1.416(11)

N(1E)-C(2E) 1.413(9)

N(1E)-C(6E) 1.482(8)

N(1E)-S(7E) 1.707(6)

C(2E)-O(2E) 1.204(8)

Appendix

230

C(2E)-C(3E) 1.495(9)

C(3E)-C(4E) 1.522(9)

C(4E)-C(5E) 1.548(9)

C(4E)-S(17E) 1.819(7)

C(5E)-C(6E) 1.515(8)

C(5E)-C(26E) 1.546(8)

C(6E)-C(28E) 1.562(8)

S(7E)-O(9E) 1.419(5)

S(7E)-O(8E) 1.433(5)

S(7E)-C(10E) 1.752(7)

C(10E)-C(11E) 1.378(9)

C(10E)-C(15E) 1.381(9)

C(11E)-C(12E) 1.384(9)

C(12E)-C(13E) 1.383(11)

C(13E)-C(14E) 1.411(10)

C(13E)-C(16E) 1.495(10)

C(14E)-C(15E) 1.365(9)

S(17E)-O(18E) 1.421(5)

S(17E)-O(19E) 1.440(5)

S(17E)-C(20E) 1.717(8)

C(20E)-C(21E) 1.369(9)

C(20E)-C(25E) 1.387(10)

C(21E)-C(22E) 1.387(10)

C(22E)-C(23E) 1.377(11)

C(23E)-C(24E) 1.384(11)

C(24E)-C(25E) 1.382(11)

C(26E)-O(27E) 1.370(7)

C(28E)-C(29E) 1.475(9)

C(29E)-C(30E) 1.397(10)

C(29E)-C(37E) 1.422(9)

Appendix

231

C(30E)-N(31E) 1.404(9)

N(31E)-C(32E) 1.350(9)

N(31E)-C(38E) 1.473(9)

C(32E)-C(33E) 1.362(10)

C(32E)-C(37E) 1.449(9)

C(33E)-C(34E) 1.355(10)

C(34E)-C(35E) 1.398(10)

C(35E)-C(36E) 1.380(10)

C(36E)-C(37E) 1.392(9)

N(1F)-C(2F) 1.324(9)

N(1F)-C(6F) 1.474(8)

N(1F)-S(7F) 1.689(6)

C(2F)-O(2F) 1.212(8)

C(2F)-C(3F) 1.547(10)

C(3F)-C(4F) 1.562(9)

C(4F)-C(5F) 1.504(9)

C(4F)-S(17F) 1.809(7)

C(5F)-C(6F) 1.515(9)

C(5F)-C(26F) 1.542(7)

C(5F)-C(26L) 1.568(9)

C(6F)-C(28F) 1.539(8)

S(7F)-O(8F) 1.426(5)

S(7F)-O(9F) 1.438(5)

S(7F)-C(10F) 1.766(7)

C(10F)-C(11F) 1.378(9)

C(10F)-C(15F) 1.390(10)

C(11F)-C(12F) 1.378(10)

C(12F)-C(13F) 1.363(11)

C(13F)-C(14F) 1.398(10)

C(13F)-C(16F) 1.495(10)

Appendix

232

C(14F)-C(15F) 1.398(9)

S(17F)-O(18F) 1.434(5)

S(17F)-O(19F) 1.445(6)

S(17F)-C(20F) 1.749(8)

C(20F)-C(21F) 1.383(10)

C(20F)-C(25F) 1.387(10)

C(21F)-C(22F) 1.403(12)

C(22F)-C(23F) 1.322(12)

C(23F)-C(24F) 1.366(11)

C(24F)-C(25F) 1.393(11)

C(26F)-O(27F) 1.409(8)

C(26L)-O(27L) 1.431(10)

C(28F)-C(29F) 1.475(9)

C(29F)-C(30F) 1.355(10)

C(29F)-C(37F) 1.402(10)

C(30F)-N(31F) 1.373(9)

N(31F)-C(32F) 1.376(9)

N(31F)-C(38F) 1.474(9)

C(32F)-C(33F) 1.360(10)

C(32F)-C(37F) 1.395(9)

C(33F)-C(34F) 1.410(11)

C(34F)-C(35F) 1.416(11)

C(35F)-C(36F) 1.364(10)

C(36F)-C(37F) 1.420(10)

C(2A)-N(1A)-C(6A) 122.3(6)

C(2A)-N(1A)-S(7A) 118.7(5)

C(6A)-N(1A)-S(7A) 119.0(5)

O(2A)-C(2A)-N(1A) 123.8(7)

O(2A)-C(2A)-C(3A) 121.5(6)

Appendix

233

N(1A)-C(2A)-C(3A) 114.5(6)

C(2A)-C(3A)-C(4A) 113.2(6)

C(3A)-C(4A)-C(5A) 116.6(5)

C(3A)-C(4A)-S(17A) 112.8(5)

C(5A)-C(4A)-S(17A) 111.0(5)

C(26A)-C(5A)-C(6A) 113.2(6)

C(26A)-C(5A)-C(4A) 108.0(5)

C(6A)-C(5A)-C(4A) 111.0(6)

N(1A)-C(6A)-C(5A) 108.8(5)

N(1A)-C(6A)-C(28A) 111.5(5)

C(5A)-C(6A)-C(28A) 112.7(6)

O(8A)-S(7A)-O(9A) 119.6(3)

O(8A)-S(7A)-N(1A) 105.2(3)

O(9A)-S(7A)-N(1A) 107.7(3)

O(8A)-S(7A)-C(10A) 108.2(3)

O(9A)-S(7A)-C(10A) 110.0(3)

N(1A)-S(7A)-C(10A) 105.0(3)

C(15A)-C(10A)-C(11A) 117.5(7)

C(15A)-C(10A)-S(7A) 120.7(6)

C(11A)-C(10A)-S(7A) 121.5(6)

C(12A)-C(11A)-C(10A) 120.5(8)

C(13A)-C(12A)-C(11A) 121.7(7)

C(14A)-C(13A)-C(12A) 118.6(7)

C(14A)-C(13A)-C(16A) 120.5(8)

C(12A)-C(13A)-C(16A) 120.8(7)

C(13A)-C(14A)-C(15A) 119.5(8)

C(10A)-C(15A)-C(14A) 121.9(7)

O(19A)-S(17A)-O(18A) 117.6(3)

O(19A)-S(17A)-C(20A) 108.2(3)

O(18A)-S(17A)-C(20A) 109.8(3)

Appendix

234

O(19A)-S(17A)-C(4A) 107.7(3)

O(18A)-S(17A)-C(4A) 107.8(3)

C(20A)-S(17A)-C(4A) 105.0(3)

C(21A)-C(20A)-C(25A) 121.9(8)

C(21A)-C(20A)-S(17A) 120.6(6)

C(25A)-C(20A)-S(17A) 117.4(6)

C(20A)-C(21A)-C(22A) 117.2(8)

C(23A)-C(22A)-C(21A) 123.8(9)

C(22A)-C(23A)-C(24A) 118.8(9)

C(23A)-C(24A)-C(25A) 122.3(8)

C(24A)-C(25A)-C(20A) 115.9(7)

O(27A)-C(26A)-C(5A) 108.7(5)

C(29A)-C(28A)-C(6A) 113.0(5)

C(30A)-C(29A)-C(37A) 105.3(6)

C(30A)-C(29A)-C(28A) 125.3(7)

C(37A)-C(29A)-C(28A) 129.4(6)

C(29A)-C(30A)-N(31A) 109.8(6)

C(32A)-N(31A)-C(30A) 110.3(6)

C(32A)-N(31A)-C(38A) 124.8(7)

C(30A)-N(31A)-C(38A) 124.9(7)

N(31A)-C(32A)-C(33A) 132.0(7)

N(31A)-C(32A)-C(37A) 106.0(7)

C(33A)-C(32A)-C(37A) 122.0(7)

C(32A)-C(33A)-C(34A) 117.7(7)

C(35A)-C(34A)-C(33A) 119.7(8)

C(36A)-C(35A)-C(34A) 122.3(8)

C(35A)-C(36A)-C(37A) 118.8(7)

C(36A)-C(37A)-C(32A) 119.5(6)

C(36A)-C(37A)-C(29A) 131.8(7)

C(32A)-C(37A)-C(29A) 108.7(6)

Appendix

235

C(2B)-N(1B)-C(6B) 121.6(6)

C(2B)-N(1B)-S(7B) 119.3(5)

C(6B)-N(1B)-S(7B) 119.1(5)

O(2B)-C(2B)-N(1B) 122.2(6)

O(2B)-C(2B)-C(3B) 123.1(7)

N(1B)-C(2B)-C(3B) 114.7(6)

C(2B)-C(3B)-C(4B) 112.5(6)

C(5B)-C(4B)-C(3B) 115.9(5)

C(5B)-C(4B)-S(17B) 109.8(4)

C(3B)-C(4B)-S(17B) 109.5(5)

C(4B)-C(5B)-C(6B) 113.5(5)

C(4B)-C(5B)-C(26B) 106.6(6)

C(6B)-C(5B)-C(26B) 111.3(6)

N(1B)-C(6B)-C(5B) 109.1(5)

N(1B)-C(6B)-C(28B) 110.0(5)

C(5B)-C(6B)-C(28B) 112.0(6)

O(9B)-S(7B)-O(8B) 120.4(3)

O(9B)-S(7B)-N(1B) 107.1(3)

O(8B)-S(7B)-N(1B) 104.9(3)

O(9B)-S(7B)-C(10B) 107.9(3)

O(8B)-S(7B)-C(10B) 108.1(3)

N(1B)-S(7B)-C(10B) 107.9(3)

C(15B)-C(10B)-C(11B) 121.2(6)

C(15B)-C(10B)-S(7B) 122.0(5)

C(11B)-C(10B)-S(7B) 116.8(6)

C(12B)-C(11B)-C(10B) 117.7(7)

C(11B)-C(12B)-C(13B) 122.3(7)

C(12B)-C(13B)-C(14B) 118.0(7)

C(12B)-C(13B)-C(16B) 121.8(7)

C(14B)-C(13B)-C(16B) 120.3(7)

Appendix

236

C(15B)-C(14B)-C(13B) 120.3(7)

C(14B)-C(15B)-C(10B) 120.4(6)

O(19B)-S(17B)-O(18B) 118.4(3)

O(19B)-S(17B)-C(20B) 106.7(3)

O(18B)-S(17B)-C(20B) 109.9(3)

O(19B)-S(17B)-C(4B) 107.2(3)

O(18B)-S(17B)-C(4B) 110.0(3)

C(20B)-S(17B)-C(4B) 103.6(3)

C(25B)-C(20B)-C(21B) 118.1(7)

C(25B)-C(20B)-S(17B) 121.6(6)

C(21B)-C(20B)-S(17B) 120.2(5)

C(20B)-C(21B)-C(22B) 119.4(7)

C(23B)-C(22B)-C(21B) 119.2(8)

C(24B)-C(23B)-C(22B) 121.9(9)

C(23B)-C(24B)-C(25B) 117.8(7)

C(24B)-C(25B)-C(20B) 123.6(8)

O(27B)-C(26B)-C(5B) 106.8(6)

C(29B)-C(28B)-C(6B) 112.8(5)

C(30B)-C(29B)-C(37B) 106.1(6)

C(30B)-C(29B)-C(28B) 127.8(7)

C(37B)-C(29B)-C(28B) 126.1(6)

C(29B)-C(30B)-N(31B) 109.6(7)

C(32B)-N(31B)-C(30B) 109.1(6)

C(32B)-N(31B)-C(38B) 126.8(7)

C(30B)-N(31B)-C(38B) 124.1(7)

N(31B)-C(32B)-C(33B) 130.1(7)

N(31B)-C(32B)-C(37B) 105.4(6)

C(33B)-C(32B)-C(37B) 124.4(7)

C(34B)-C(33B)-C(32B) 117.7(7)

C(33B)-C(34B)-C(35B) 120.2(8)

Appendix

237

C(36B)-C(35B)-C(34B) 120.4(8)

C(37B)-C(36B)-C(35B) 121.7(7)

C(36B)-C(37B)-C(29B) 134.7(7)

C(36B)-C(37B)-C(32B) 115.5(7)

C(29B)-C(37B)-C(32B) 109.8(6)

C(2C)-N(1C)-C(6C) 120.5(6)

C(2C)-N(1C)-S(7C) 120.1(5)

C(6C)-N(1C)-S(7C) 119.4(5)

O(2C)-C(2C)-N(1C) 123.0(8)

O(2C)-C(2C)-C(3C) 118.6(8)

N(1C)-C(2C)-C(3C) 118.3(7)

C(2C)-C(3C)-C(4C) 111.4(7)

C(5C)-C(4C)-C(3C) 115.6(6)

C(5C)-C(4C)-S(17C) 110.9(5)

C(3C)-C(4C)-S(17C) 110.3(5)

C(4C)-C(5C)-C(26C) 114.8(7)

C(4C)-C(5C)-C(6C) 114.3(6)

C(26C)-C(5C)-C(6C) 103.8(7)

C(4C)-C(5C)-C(26I) 105.1(6)

C(26C)-C(5C)-C(26I) 9.8(8)

C(6C)-C(5C)-C(26I) 109.4(9)

N(1C)-C(6C)-C(28C) 114.5(5)

N(1C)-C(6C)-C(5C) 107.6(5)

C(28C)-C(6C)-C(5C) 111.9(6)

O(9C)-S(7C)-O(8C) 118.6(3)

O(9C)-S(7C)-N(1C) 108.1(3)

O(8C)-S(7C)-N(1C) 104.6(3)

O(9C)-S(7C)-C(10C) 109.0(4)

O(8C)-S(7C)-C(10C) 109.7(3)

N(1C)-S(7C)-C(10C) 106.0(3)

Appendix

238

C(15C)-C(10C)-C(11C) 122.4(7)

C(15C)-C(10C)-S(7C) 119.5(6)

C(11C)-C(10C)-S(7C) 118.1(6)

C(10C)-C(11C)-C(12C) 117.9(8)

C(13C)-C(12C)-C(11C) 120.2(7)

C(14C)-C(13C)-C(12C) 119.3(8)

C(14C)-C(13C)-C(16C) 121.7(9)

C(12C)-C(13C)-C(16C) 119.0(8)

C(13C)-C(14C)-C(15C) 123.3(8)

C(10C)-C(15C)-C(14C) 117.0(7)

O(19C)-S(17C)-O(18C) 118.4(4)

O(19C)-S(17C)-C(20C) 108.9(4)

O(18C)-S(17C)-C(20C) 108.5(4)

O(19C)-S(17C)-C(4C) 106.5(4)

O(18C)-S(17C)-C(4C) 108.9(3)

C(20C)-S(17C)-C(4C) 104.8(4)

C(25C)-C(20C)-C(21C) 121.9(8)

C(25C)-C(20C)-S(17C) 117.6(7)

C(21C)-C(20C)-S(17C) 120.4(6)

C(20C)-C(21C)-C(22C) 120.0(8)

C(21C)-C(22C)-C(23C) 117.5(9)

C(24C)-C(23C)-C(22C) 122.3(9)

C(25C)-C(24C)-C(23C) 119.1(9)

C(20C)-C(25C)-C(24C) 118.9(9)

O(27C)-C(26C)-C(5C) 115.7(9)

O(27I)-C(26I)-C(5C) 106.1(9)

C(29C)-C(28C)-C(6C) 115.4(5)

C(30C)-C(29C)-C(37C) 108.0(7)

C(30C)-C(29C)-C(28C) 127.0(7)

C(37C)-C(29C)-C(28C) 125.0(7)

Appendix

239

N(31C)-C(30C)-C(29C) 109.7(7)

C(30C)-N(31C)-C(32C) 106.8(6)

C(30C)-N(31C)-C(38C) 125.5(7)

C(32C)-N(31C)-C(38C) 127.5(7)

C(37C)-C(32C)-N(31C) 110.5(7)

C(37C)-C(32C)-C(33C) 121.1(8)

N(31C)-C(32C)-C(33C) 128.3(8)

C(34C)-C(33C)-C(32C) 116.3(8)

C(33C)-C(34C)-C(35C) 123.0(8)

C(36C)-C(35C)-C(34C) 120.6(8)

C(35C)-C(36C)-C(37C) 117.8(8)

C(36C)-C(37C)-C(32C) 121.1(8)

C(36C)-C(37C)-C(29C) 134.0(8)

C(32C)-C(37C)-C(29C) 104.8(7)

C(2D)-N(1D)-C(6D) 119.6(6)

C(2D)-N(1D)-S(7D) 121.5(6)

C(6D)-N(1D)-S(7D) 118.7(5)

O(2D)-C(2D)-N(1D) 117.7(8)

O(2D)-C(2D)-C(3D) 124.7(7)

N(1D)-C(2D)-C(3D) 117.5(7)

C(2D)-C(3D)-C(4D) 110.9(7)

C(3D)-C(4D)-C(5D) 115.5(6)

C(3D)-C(4D)-S(17D) 110.3(5)

C(5D)-C(4D)-S(17D) 108.2(5)

C(26D)-C(5D)-C(26J) 10.2(8)

C(26D)-C(5D)-C(6D) 111.4(8)

C(26J)-C(5D)-C(6D) 101.4(7)

C(26D)-C(5D)-C(4D) 105.1(6)

C(26J)-C(5D)-C(4D) 112.1(9)

C(6D)-C(5D)-C(4D) 113.0(6)

Appendix

240

N(1D)-C(6D)-C(28D) 111.5(5)

N(1D)-C(6D)-C(5D) 108.9(6)

C(28D)-C(6D)-C(5D) 112.7(6)

O(8D)-S(7D)-O(9D) 117.6(3)

O(8D)-S(7D)-N(1D) 106.0(3)

O(9D)-S(7D)-N(1D) 108.2(3)

O(8D)-S(7D)-C(10D) 109.3(3)

O(9D)-S(7D)-C(10D) 109.2(4)

N(1D)-S(7D)-C(10D) 105.9(3)

C(15D)-C(10D)-C(11D) 119.3(7)

C(15D)-C(10D)-S(7D) 120.6(6)

C(11D)-C(10D)-S(7D) 119.1(6)

C(10D)-C(11D)-C(12D) 120.8(7)

C(13D)-C(12D)-C(11D) 119.3(7)

C(14D)-C(13D)-C(12D) 118.8(8)

C(14D)-C(13D)-C(16D) 121.9(8)

C(12D)-C(13D)-C(16D) 119.3(8)

C(13D)-C(14D)-C(15D) 121.7(8)

C(10D)-C(15D)-C(14D) 119.8(8)

O(19D)-S(17D)-O(18D) 118.2(4)

O(19D)-S(17D)-C(20D) 108.9(4)

O(18D)-S(17D)-C(20D) 109.9(4)

O(19D)-S(17D)-C(4D) 106.6(4)

O(18D)-S(17D)-C(4D) 108.7(3)

C(20D)-S(17D)-C(4D) 103.6(3)

C(21D)-C(20D)-C(25D) 123.5(8)

C(21D)-C(20D)-S(17D) 120.4(6)

C(25D)-C(20D)-S(17D) 116.1(7)

C(20D)-C(21D)-C(22D) 117.0(7)

C(23D)-C(22D)-C(21D) 120.6(8)

Appendix

241

C(22D)-C(23D)-C(24D) 120.1(8)

C(25D)-C(24D)-C(23D) 121.7(8)

C(24D)-C(25D)-C(20D) 116.9(8)

O(27D)-C(26D)-C(5D) 107.7(8)

O(27J)-C(26J)-C(5D) 119.7(11)

C(29D)-C(28D)-C(6D) 112.8(6)

C(30D)-C(29D)-C(37D) 105.6(7)

C(30D)-C(29D)-C(28D) 131.1(7)

C(37D)-C(29D)-C(28D) 123.3(7)

N(31D)-C(30D)-C(29D) 111.0(7)

C(30D)-N(31D)-C(32D) 108.3(7)

C(30D)-N(31D)-C(38D) 125.1(7)

C(32D)-N(31D)-C(38D) 126.5(7)

N(31D)-C(32D)-C(37D) 108.6(7)

N(31D)-C(32D)-C(33D) 128.6(7)

C(37D)-C(32D)-C(33D) 122.7(8)

C(34D)-C(33D)-C(32D) 115.4(8)

C(33D)-C(34D)-C(35D) 124.7(8)

C(36D)-C(35D)-C(34D) 119.4(8)

C(35D)-C(36D)-C(37D) 120.4(9)

C(32D)-C(37D)-C(36D) 117.4(8)

C(32D)-C(37D)-C(29D) 106.4(7)

C(36D)-C(37D)-C(29D) 136.2(8)

C(2E)-N(1E)-C(6E) 122.8(6)

C(2E)-N(1E)-S(7E) 116.2(5)

C(6E)-N(1E)-S(7E) 120.5(5)

O(2E)-C(2E)-N(1E) 122.8(7)

O(2E)-C(2E)-C(3E) 125.9(7)

N(1E)-C(2E)-C(3E) 110.9(7)

C(2E)-C(3E)-C(4E) 114.1(6)

Appendix

242

C(3E)-C(4E)-C(5E) 115.9(6)

C(3E)-C(4E)-S(17E) 111.1(5)

C(5E)-C(4E)-S(17E) 110.2(5)

C(6E)-C(5E)-C(26E) 108.3(6)

C(6E)-C(5E)-C(4E) 110.6(5)

C(26E)-C(5E)-C(4E) 112.8(6)

N(1E)-C(6E)-C(5E) 109.5(5)

N(1E)-C(6E)-C(28E) 109.8(5)

C(5E)-C(6E)-C(28E) 114.9(6)

O(9E)-S(7E)-O(8E) 117.2(3)

O(9E)-S(7E)-N(1E) 108.9(3)

O(8E)-S(7E)-N(1E) 103.6(3)

O(9E)-S(7E)-C(10E) 110.1(3)

O(8E)-S(7E)-C(10E) 109.2(3)

N(1E)-S(7E)-C(10E) 107.3(3)

C(11E)-C(10E)-C(15E) 121.0(7)

C(11E)-C(10E)-S(7E) 119.0(6)

C(15E)-C(10E)-S(7E) 120.0(5)

C(10E)-C(11E)-C(12E) 117.7(7)

C(13E)-C(12E)-C(11E) 123.3(8)

C(12E)-C(13E)-C(14E) 116.8(7)

C(12E)-C(13E)-C(16E) 121.1(8)

C(14E)-C(13E)-C(16E) 122.1(9)

C(15E)-C(14E)-C(13E) 120.7(7)

C(14E)-C(15E)-C(10E) 120.4(7)

O(18E)-S(17E)-O(19E) 119.4(4)

O(18E)-S(17E)-C(20E) 108.8(4)

O(19E)-S(17E)-C(20E) 107.9(4)

O(18E)-S(17E)-C(4E) 108.3(3)

O(19E)-S(17E)-C(4E) 106.9(3)

Appendix

243

C(20E)-S(17E)-C(4E) 104.7(3)

C(21E)-C(20E)-C(25E) 118.3(8)

C(21E)-C(20E)-S(17E) 121.1(6)

C(25E)-C(20E)-S(17E) 120.6(6)

C(20E)-C(21E)-C(22E) 119.8(8)

C(23E)-C(22E)-C(21E) 121.2(8)

C(22E)-C(23E)-C(24E) 120.0(9)

C(25E)-C(24E)-C(23E) 117.7(9)

C(24E)-C(25E)-C(20E) 122.9(9)

O(27E)-C(26E)-C(5E) 113.6(7)

C(29E)-C(28E)-C(6E) 110.5(5)

C(30E)-C(29E)-C(37E) 106.6(6)

C(30E)-C(29E)-C(28E) 126.5(7)

C(37E)-C(29E)-C(28E) 126.9(7)

C(29E)-C(30E)-N(31E) 107.4(7)

C(32E)-N(31E)-C(30E) 112.3(6)

C(32E)-N(31E)-C(38E) 126.7(7)

C(30E)-N(31E)-C(38E) 121.0(7)

N(31E)-C(32E)-C(33E) 132.8(7)

N(31E)-C(32E)-C(37E) 105.0(7)

C(33E)-C(32E)-C(37E) 122.2(7)

C(34E)-C(33E)-C(32E) 118.5(7)

C(33E)-C(34E)-C(35E) 121.7(9)

C(36E)-C(35E)-C(34E) 120.7(8)

C(35E)-C(36E)-C(37E) 119.6(7)

C(36E)-C(37E)-C(29E) 134.0(7)

C(36E)-C(37E)-C(32E) 117.2(7)

C(29E)-C(37E)-C(32E) 108.8(7)

C(2F)-N(1F)-C(6F) 120.1(7)

C(2F)-N(1F)-S(7F) 117.9(5)

Appendix

244

C(6F)-N(1F)-S(7F) 121.5(6)

O(2F)-C(2F)-N(1F) 125.9(8)

O(2F)-C(2F)-C(3F) 117.7(8)

N(1F)-C(2F)-C(3F) 116.5(6)

C(2F)-C(3F)-C(4F) 110.7(6)

C(5F)-C(4F)-C(3F) 115.8(6)

C(5F)-C(4F)-S(17F) 111.2(5)

C(3F)-C(4F)-S(17F) 109.8(5)

C(4F)-C(5F)-C(6F) 111.9(6)

C(4F)-C(5F)-C(26F) 116.2(6)

C(6F)-C(5F)-C(26F) 107.2(6)

C(4F)-C(5F)-C(26L) 106.9(8)

C(6F)-C(5F)-C(26L) 107.5(10)

C(26F)-C(5F)-C(26L) 11.0(9)

N(1F)-C(6F)-C(5F) 109.9(6)

N(1F)-C(6F)-C(28F) 112.9(6)

C(5F)-C(6F)-C(28F) 114.8(6)

O(8F)-S(7F)-O(9F) 119.9(3)

O(8F)-S(7F)-N(1F) 103.8(3)

O(9F)-S(7F)-N(1F) 108.8(3)

O(8F)-S(7F)-C(10F) 106.4(3)

O(9F)-S(7F)-C(10F) 109.3(3)

N(1F)-S(7F)-C(10F) 108.0(3)

C(11F)-C(10F)-C(15F) 121.7(7)

C(11F)-C(10F)-S(7F) 118.7(6)

C(15F)-C(10F)-S(7F) 119.6(6)

C(12F)-C(11F)-C(10F) 116.6(8)

C(13F)-C(12F)-C(11F) 124.5(8)

C(12F)-C(13F)-C(14F) 118.3(7)

C(12F)-C(13F)-C(16F) 122.3(8)

Appendix

245

C(14F)-C(13F)-C(16F) 119.4(8)

C(13F)-C(14F)-C(15F) 119.3(8)

C(10F)-C(15F)-C(14F) 119.6(7)

O(18F)-S(17F)-O(19F) 119.5(4)

O(18F)-S(17F)-C(20F) 109.7(4)

O(19F)-S(17F)-C(20F) 107.5(4)

O(18F)-S(17F)-C(4F) 108.1(4)

O(19F)-S(17F)-C(4F) 105.9(4)

C(20F)-S(17F)-C(4F) 105.2(4)

C(21F)-C(20F)-C(25F) 120.3(9)

C(21F)-C(20F)-S(17F) 120.5(7)

C(25F)-C(20F)-S(17F) 119.2(7)

C(20F)-C(21F)-C(22F) 121.1(9)

C(23F)-C(22F)-C(21F) 117.3(10)

C(22F)-C(23F)-C(24F) 123.1(11)

C(23F)-C(24F)-C(25F) 121.0(9)

C(20F)-C(25F)-C(24F) 116.9(8)

O(27F)-C(26F)-C(5F) 113.0(7)

O(27L)-C(26L)-C(5F) 102.6(12)

C(29F)-C(28F)-C(6F) 113.4(6)

C(30F)-C(29F)-C(37F) 105.8(7)

C(30F)-C(29F)-C(28F) 126.4(8)

C(37F)-C(29F)-C(28F) 127.8(7)

C(29F)-C(30F)-N(31F) 110.4(8)

C(30F)-N(31F)-C(32F) 108.4(7)

C(30F)-N(31F)-C(38F) 127.5(7)

C(32F)-N(31F)-C(38F) 124.0(7)

C(33F)-C(32F)-N(31F) 130.6(8)

C(33F)-C(32F)-C(37F) 123.1(8)

N(31F)-C(32F)-C(37F) 106.3(7)

Appendix

246

C(32F)-C(33F)-C(34F) 118.1(8)

C(33F)-C(34F)-C(35F) 120.2(8)

C(36F)-C(35F)-C(34F) 120.4(8)

C(35F)-C(36F)-C(37F) 119.9(7)

C(32F)-C(37F)-C(29F) 109.1(7)

C(32F)-C(37F)-C(36F) 118.3(7)

C(29F)-C(37F)-C(36F) 132.5(7)

Appendix

247

4.1.4. 4-Methyl-N-((S)-2-(1-methyl-1H-indol-3-yl)-1-((3R,4R)-6-oxo-4-

(phenylsulfonyl)tetrahydro-2H-pyran-3-yl)ethyl)benzenesulfonamide (133)

Table 1. Crystal data and structure refinement for 133.


Formula C29 H32 N2 O7 S


Appendix

248

Temperature 173 K




b = 10.4773(4) Å = 74.919(4)°

c = 13.9025(6) Å = 67.702(4)°

Volume, Z 1321.60(11) Å3, 2



F(000) 584

Crystal colour / morphology Colourless tabular needles



Index ranges -13<=h<=15, -15<=k<=15, -20<=l<=19










Appendix

249




N(1)-C(2) 1.3963(15)

N(1)-C(6) 1.4940(15)

N(1)-S(7) 1.6962(10)

C(2)-O(2) 1.2209(15)

C(2)-C(3) 1.5144(17)

C(3)-C(4) 1.5317(17)

C(4)-C(17) 1.5006(16)

C(4)-C(5) 1.5419(17)

C(5)-C(28) 1.5231(16)

C(5)-C(6) 1.5314(16)

C(6)-C(26) 1.5366(17)

S(7)-O(9) 1.4296(10)

S(7)-O(8) 1.4366(10)

S(7)-C(10) 1.7553(13)

C(10)-C(15) 1.3842(18)

C(10)-C(11) 1.3916(18)

C(11)-C(12) 1.3871(19)

C(12)-C(13) 1.394(2)

C(13)-C(14) 1.393(2)

C(13)-C(16) 1.507(2)

C(14)-C(15) 1.3901(18)

C(17)-C(25) 1.3699(17)

C(17)-N(18) 1.3890(15)

N(18)-C(19) 1.3843(16)

N(18)-C(27) 1.4471(18)

C(19)-C(20) 1.4004(17)

Appendix

250

C(19)-C(24) 1.410(2)

C(20)-C(21) 1.385(2)

C(21)-C(22) 1.402(3)

C(22)-C(23) 1.383(2)

C(23)-C(24) 1.4023(19)

C(24)-C(25) 1.4345(17)

C(25)-C(26) 1.4962(17)

C(28)-O(29) 1.4521(15)

O(29)-C(30) 1.3445(15)

C(30)-O(30) 1.2041(18)

C(30)-C(31) 1.5060(19)

C(31)-C(32) 1.549(2)

C(32)-O(36) 1.4160(17)

C(32)-O(33) 1.4214(17)

C(32)-C(37) 1.517(2)

O(33)-C(34) 1.428(2)

C(34)-C(35) 1.526(2)

C(35)-O(36) 1.4233(18)

C(2)-N(1)-C(6) 125.12(10)

C(2)-N(1)-S(7) 117.45(8)

C(6)-N(1)-S(7) 116.58(8)

O(2)-C(2)-N(1) 120.52(11)

O(2)-C(2)-C(3) 121.48(11)

N(1)-C(2)-C(3) 117.89(10)

C(2)-C(3)-C(4) 114.13(10)

C(17)-C(4)-C(3) 108.79(10)

C(17)-C(4)-C(5) 107.62(10)

C(3)-C(4)-C(5) 109.34(9)

C(28)-C(5)-C(6) 113.62(10)

Appendix

251

C(28)-C(5)-C(4) 111.31(10)

C(6)-C(5)-C(4) 108.76(9)

N(1)-C(6)-C(5) 109.68(9)

N(1)-C(6)-C(26) 110.88(10)

C(5)-C(6)-C(26) 110.45(9)

O(9)-S(7)-O(8) 118.60(7)

O(9)-S(7)-N(1) 110.04(6)

O(8)-S(7)-N(1) 104.12(6)

O(9)-S(7)-C(10) 110.24(6)

O(8)-S(7)-C(10) 108.56(6)

N(1)-S(7)-C(10) 104.21(5)

C(15)-C(10)-C(11) 121.45(12)

C(15)-C(10)-S(7) 120.08(10)

C(11)-C(10)-S(7) 118.39(10)

C(12)-C(11)-C(10) 118.63(13)

C(11)-C(12)-C(13) 121.21(13)

C(14)-C(13)-C(12) 118.71(12)

C(14)-C(13)-C(16) 120.59(14)

C(12)-C(13)-C(16) 120.71(13)

C(15)-C(14)-C(13) 121.00(13)

C(10)-C(15)-C(14) 118.90(12)

C(25)-C(17)-N(18) 110.08(10)

C(25)-C(17)-C(4) 125.12(11)

N(18)-C(17)-C(4) 124.36(11)

C(19)-N(18)-C(17) 107.87(11)

C(19)-N(18)-C(27) 124.96(11)

C(17)-N(18)-C(27) 127.16(11)

N(18)-C(19)-C(20) 129.59(14)

N(18)-C(19)-C(24) 108.30(11)

C(20)-C(19)-C(24) 122.10(13)

Appendix

252

C(21)-C(20)-C(19) 117.14(15)

C(20)-C(21)-C(22) 121.56(13)

C(23)-C(22)-C(21) 121.15(14)

C(22)-C(23)-C(24) 118.70(15)

C(23)-C(24)-C(19) 119.35(12)

C(23)-C(24)-C(25) 133.78(13)

C(19)-C(24)-C(25) 106.84(11)

C(17)-C(25)-C(24) 106.91(11)

C(17)-C(25)-C(26) 122.61(11)

C(24)-C(25)-C(26) 130.39(11)

C(25)-C(26)-C(6) 110.11(10)

O(29)-C(28)-C(5) 107.35(10)

C(30)-O(29)-C(28) 114.41(10)

O(30)-C(30)-O(29) 123.13(13)

O(30)-C(30)-C(31) 124.30(12)

O(29)-C(30)-C(31) 112.55(12)

C(30)-C(31)-C(32) 111.25(11)

O(36)-C(32)-O(33) 105.06(11)

O(36)-C(32)-C(37) 108.86(12)

O(33)-C(32)-C(37) 108.94(13)

O(36)-C(32)-C(31) 109.31(11)

O(33)-C(32)-C(31) 110.20(11)

C(37)-C(32)-C(31) 114.06(12)

C(32)-O(33)-C(34) 106.67(12)

O(33)-C(34)-C(35) 104.58(13)

O(36)-C(35)-C(34) 104.86(13)

C(32)-O(36)-C(35) 107.52(11)

Symmetry transformations used to generate equivalent atoms:

References

253

4.2 References

1 Maehr, H., J. Chem. Ed. 1985, 62, 114.

2 Keawpradub, N.; Kirby, G. C.; Steele, J. C.; Houghton, P. J., Planta Med. 1999, 65, 690.

3 (a) Bi, Y.; Zhang, L.-H.; Hamaker, L. K.; Cook, J. M., J. Am. Chem. Soc. 1994, 116, 9027; (b) Liao, X.; Zhou, H.;

Wearing, X. Z.; Ma, J.; Cook, J. M., Org. Lett. 2005, 7, 3501; (c) Liao, X.; Zhou, H.; Yu, J.; Cook, J. M., J. Org.

Chem. 2006, 71, 8884; (d) Miller, K. A.; Shanahan, C. S.; Martin, S. F., Tetrahedron 2008, 64, 6884 and references

therein; (e) Bailey, P. D.; Morgan, K. M., J. Chem. Soc. Perkin Trans. 1 2000, 3578; (f) Kuthe, J.; Wong, A.;

Davies, I. W.; Reider, P. J., Tetrahedron Lett. 2002, 43, 3871.

4 LeMen, J.; Taylor, W. I., Experientia 1965, 21, 508.

5 Trost, B. M.; Brennan, M. K., Synthesis 2009, 18, 3003.

6 (a) Kam, T.; Choo, Y. Bisindole Alkaloids, In The Alkaloids, Vol. 63; Cordell, G. A., Ed.; Academic Press: New

York, 2006, 181; (b) Saxton, J. E. Synthesis of the Aspidosperma Alkaloids, In The Alkaloids, Vol. 50; Cordell, G.

A., Ed.; Academic Press: New York, 1998, 343.

7 Stoll, A.; Hofmann, A., Helv. Chim. Acta 1953, 36, 1143.

8 (a) Bi, Y.; Hamaker, L. K.; Cook, J. M., The Synthesis of Macroline Related Indole Alkaloids in Studies in Natural

Product Chemistry 1993, 13, 383; (b) Bi, Y.; Hamaker Y.; Cook, J. M., The Synthesis of Macroline-Related Indole

Alkaloids; Studies in Natural Products Chemistry, Pergamon, London, 1994, vol. 9.

9 Hamaker, L. K.; Cook, J. M., The Synthesis of Macroline Related Sarpagine Alkaloids. Alkaloids: Chemical and

Biological Perspectives, Elsevier Science, New York, 1995, Vol. 9.

10 Lounasmaa, M.; Hanhinen, P.; Westersund, M., The Sarpagine Group of Indole Alkaloids, Academic, San Diego,

CA, 1999, Vol. 52.

11 Lounasmaa, M.; Hanhinen, P., The Ajmaline Group of Indole Alkaloids, Alkaloids, 2001, 55, 1.

12 Lewis, S. E., Tetrahedron 2006, 62, 8655.

13 Keawpradub, N.; Eno-Amooquaye, E.; Burke, P. J.; Houghton, P. J., Planta Med. 1999, 65, 311.

14 Gilman, R. E., Diss. Abs., 1959, 20, 1578.

15 Cook, J. M.; Le Quesne, P. W.; Elderfield, R. C., J. Chem. Soc. D. 1969, 22, 1306.

16 Zhang, L.-H.; Cook, J. M., J. Am. Chem. Soc. 1990, 112, 4088.

17 Gan, T.; Cook, J. M., Tetrahedron Lett. 1996, 37, 5033; (b) Gan, T.; Cook, J. M., J. Org. Chem. 1998, 63, 1478.

18 Gan, T.; Cook, J. M., Tetrahedron Lett. 1996, 37, 5037.

19 Li, J.; Cook, J. M., J. Org. Chem. 1998, 63, 4166.

20 Li, J.; Wang, T.; Yu, P.; Peterson, A.; Weber, R.; Soerens, D.; Grubisha, D.; Bennett, D.; Cook, J. M., J. Am.

Chem. Soc. 1999, 121, 6998.

21 Wang, T.; Xu, Q.; Yu, P.; Liu, X.; Cook, J. M., Org. Lett. 2001, 3, 345.

22 For a review on the Pictet–Spengler condensation, see Cook, J. M.; Cox, E. D. Chem. Rev. 1995, 95, 1797.

23 (a) Jawdosiuk, M.; Cook, J. M., J. Org. Chem. 1984, 49, 2699; (b) Ungemach, F.; DiPierro, M.; Weber, R.; Cook,

J. M., J. Org. Chem. 1981, 46, 164; (c) Czerwinski, K. M.; Deng, L.; Cook, J. M., Tetrahedron Lett. 1992, 33, 4721.

References

254

24

(a) Trudell, M. L., Soerens, D.; Webber, R. W.; Hutchins, L.; Grubisha, D.; Bennett, D.; Cook, J. M., Tetrahedron

1992, 48, 1805; (b) Zhang, L-H.; Bi, Y-Z.; Yu, F-X.; Menzia, G.; Cook, J. M., Heterocycles 1992 , 34, 517.

25 Bailey, P. D.; Mclay, N. R., J. Chem. Soc. Perkin Trans. 1 1993, 441.

26 (a) Zhang, L.-H.; Cook, J. M., Heterocycles, 1988, 27, 6, 1353; (b) Zhang, L.-H.; Cook, J. M., Heterocycles, 1988,

27, 12, 2795.

27 Zhang, L.-H.; Trudell, M. L.; Hollinshead, S. P.; Cook, J. M., J. Am. Chem. Soc. 1989, 111, 8263.

28 Bi, Y.; Zhang, L.-H.; Hamaker, L. K.; Cook, J. M., J. Am. Chem. Soc. 1994, 116, 9027.

29 Liao, X.; Zhou, H.; Wearing, X. Z.; Ma, J.; Cook, J. M., Org. Lett. 2005, 7, 3501.

30 Liao, X.; Zhou, H.; Yu, J.; Cook, J. M., J. Org. Chem. 2006, 71, 8884.

31 Liu, X.; Zhang, C.; Liao, X.; Cook, J. M., Tetrahedron Lett. 2002, 43, 7373.

32 Wang, T.; Cook, J. M., Org. Lett. 2000, 2, 2057.

33 Yu, J.; Wang, T.; Liu, X.; Deschamps, J.; Flippen-Anderson, J.; Liao, X.; Cook, J. M., J. Org. Chem. 2003, 68,

7565.

34 Muratake, H.; Natsume, M., Tetrahedron Lett. 1997, 38, 7581.

35 Cao, H.; Yu, J.; Wearing, X.; Zhang, C.; Liu, X.; Deschamps, J.; Cook, J. M. Tetrahedron Lett. 2003, 44, 8013.

36 Liu, X.; Deschamp, J. R.; Cook, J. M., Org. Lett. 2002, 4, 3339.

37 Kuethe, J. T.; Wong, A.; Davies, I. W.; Reider, P. J., Tetrahedron Lett. 2002, 43, 3871.

38 Tran, Y. S.; Kwon, O., Org. Lett. 2005, 7, 4289.

39 Zhu, X.-F.; Lan, J.; Kwon, O., J. Am. Chem. Soc. 2003, 125, 4716.

40 Fukuyama, T.; Cheung, M.; Kan, T., Synlett 1999, 1301.

41 (a) Eschweiler, W., Ber. 1905, 38, 880; (b) Clarke, H. T.; Gillespie, H. B.; Weisshaus, S. Z., J. Am. Chem. Soc.

1933, 55, 4571; (c) Newman, M. S.; Lloyd, H. A., J. Am. Chem. Soc. 1952, 74, 2672.

42 Miller, K. A.; Martin, S. F., Org. Lett. 2007, 9, 1113.

43 Miller, K. A.; Shanahan, C. S.; Martin, S. F. Tetrahedron 2008, 64, 6884.

44 For reviews/reports on the synthesis and applications of aziridines, see (a) Tanner, D. Angew. Chem., Int. Ed.

Engl. 1994, 33, 599; (b) Mccoull, W.; Davis, F. A. Synthesis 2000, 1347; (c) Sweeney, J. B., Chem Soc Rev 2002,

31, 247.

45 (a) Vandekerckhove, S.; H’Hooghe, M., Bioorg. & Med. Chem. 2013, 21, 3643; (b) Bera, M.; Roy, S.,

Tetrahedron Lett. 2007, 48, 7144; (c) Chawla, R.; Singh, A. K.; Yadlav, L. D. S., RSC Advances 2013, 3, 11385.

46 (a) Craig, D.; Jones, P. S.; Rowlands, G. J., Synlett 1997, 12, 1423; (b) Berry, B.; Rowlands, G.; Craig, D.; Jones,

P. S., Chem. Commun. 1997, 2141; (c) Caldwell, J. J.; Craig, D.; East, S. P., Synlett 2001, 10, 1602.

47 (a) Craig, D.; Mccague, R.; Potter, G. A.; Williams, M. R. V., Synlett 1998, 1, 55; (b) Craig, D.; Mccague, R.;

Potter, G. A.; Williams, M. R. V., Synlett 1998, 1, 58; c) Adelbrecht, J.-C.; Craig, D.; Dymock, B. W.; Thorimbert,

S., Synlett 2000, 4, 467.

48 Pak, C. S.; Lee, G. H., J. Org. Chem. 1991, 56, 1128.

49 Toyooka, N.; Zhou, D.; Nemoto, H., J. Org. Chem. 2008, 73, 4575.

References

255

50

Biard, J. F.; Guyot, S.; Roussakis, C.; Verbist, J. F.; Vercuateren, J.; Wber, J. F.; Boukef, K., Tetrahedron Lett.

1994, 35, 2691.

51 Berry, M. B.; Rowlands, G. J.; Craig, D.; Jones, P. S., Chem. Commun. 1997, 22, 2141.

52 Caldwell, J. J.; Craig, D., Angew. Chem., Int. Ed. Engl. 2007, 119, 2685.

53 Adelbrecht, J.-C.; Craig, D.; Thorimbert, S., Tetrahedron Lett. 2001, 42, 8369.

54 Adelbrecht, J.-C.; Craig, D.; Flemming, A. J.; Martin, F. M., Synlett 2005, 17, 2643.

55 Carballares, S.; Craig, D.; Hyland, C. J. T.; Lu, P.; Mathie, T.; White, A. J. P., Chem. Commun. 2009, 4, 451.

56 Lewis, S. E. Ph.D Thesis, Imperial College London, 2005.

57 Tholen, N. T. H., Ph.D Thesis, Imperial College London, 2010.

58 Ioannidis, S., Ph.D Thesis, University of London, 1999.

59 For the use of TMSI for cleaving ethers, see Jung, M. E.; Andrus, W. A.; Ornstein, P. L., Tetrahedron Lett. 1977,

18, 4175.

60 Hwu, J. R., J. Org. Chem. 1983, 48, 4432.

61 Maruoka, K.; Concepcion, A. B.; Murase, N.; Oishi, M.; Hirayama, N.; Yamamoto, H., J. Am. Chem. Soc. 1993,

115, 3943.

62 Rahn, V. S., Ph.D Thesis, Imperial College London, 2002.

63 (a) Schlosser, M.; Coffinet, D., Synthesis 1971, 7, 380; (b) Schlosser, M.; Titus, J.; Guggisberg, Y., Synlett 1990,

11, 704.

64 (a) Tanner, D.; Somfai, P. Tetrahedron Lett. 1987, 28, 1211; (b) Tanner, D.; Somfai, P. Tetrahedron 1988, 44,

613 (c) Tanner, D.; Somfai, P., Tetrahedron 1988, 44, 619.

65 Fuji, K.; Kawabata, T.; Kiryu, Y.; Sugiura, Y., Heterocycles 1996, 42, 701.

66 Mathie, T., Towards the Total Synthesis of Alstonerine, Craig Group internal document, 2008.

67 Carballares, S.; Craig, D.; Hyland, C. J. T.; Lu, P.; Mathie, T.; White, A. J. P., Chem. Commun. 2009, 4, 451.

68 Cox, P.; Craig, D.; Ioannidis, S. ; Rahn, V. S., Tetrahedron Lett. 2005, 46, 4687.

69 (a) Jeong, J. U.; Tao, B.; Sagasser, I; Henniges, H.; Sharpless, K. B., J. Am. Chem. Soc. 1998, 120, 6844; (b)

Ichiki, M.; Tanimoto, H.; Miwa, S.; Saito, R.; Sato, T.; Chida, N., Chemistry – A European Journal 2013, 19, 264.

70 Smith, A. B.; Kim, D.-S. Org. Lett. 2005, 7, 3247.

71 De Lombaert, S. ; Nemery, I. ; Roekens, B.; Carretero, J. C. ; Kimmel, T.; Ghosez, L., Tetrahedron Lett. 1986, 27,

5099.

72 Parham, W. E.; Schweizer, E. E., J. Org. Chem. 1959, 24, 1733.

73 Parham, W. E.; Christensen, L.; Groen, S. H.; Dodson, R. M., J. Org. Chem. 1964, 29, 2211.

74 Parham, W. E.; McKnow, W. D.; Nelson, V.; Kajigaeshi, S.; Ishikawa, N., J. Org. Chem. 1973, 38, 1361.

75 Carr, R. V. C.; Williams, R. V.; Paquette, L. A., J. Org. Chem. 1983, 48, 4976.

76 Kirner, W. R.; Richter, G. H., J. Am. Chem. Soc. 1929, 51, 3409.

77 Van Der Schaaf, P. A.; Kolly, R.; Kirner, H.-J.; Rime, F., Mühlebach, A.; Hafner, A., J. Organometallic Chem.

2000, 606, 65.

References

256

78 Russel, G. A.; Hershberger, J., J. Am. Chem. Soc. 1980, 102, 7603.

79 Cuadrado, P.; González–Nogal, A. M., Tetrahedron Lett. 2000, 41, 1111.

80 Armarego, W. L. F.; Chai, C., Purification of Laboratory Chemicals, Elsevier Science, New York, 2013, Vol. 7,

126.

81 Craig, D.; Lu, P.; Mathie, T.; Tholen, N. T. H., Tetrahedron, 2010, 66, 6376.

82 Ohno, H.; Hamaguchi, H.; Ohata, M.; Kosaka, S.; Tanaka, T., J. Am. Chem. Soc. 2004, 126, 8744.

83 Nicolaou, K.C.; Webber, S. E., Synthesis 1986, 6, 453.

84 Mohan, P.; Koushik, K.; Fuertes, M. J. Tetrahedron Lett. 2012, 53, 2730.

85 Clemens, R. J., J. Am. Chem. Soc. 1989, 11, 1989.

86 Tsunoda, T.; Suzuki, M.; Noyori, R., Tetrahedron Lett. 1980, 21, 1357.

87 Padwa, A.; Nara, S.; Wang, Q., J. Org. Chem. 2005, 70, 8538.

88 Tsunoda, T.; Suzuki, M.; Noyori, R., Tetrahedron Lett. 1980, 21, 1357.

89 Peters, S.; Eckhardt, M.; Hamilton, B. S.; Himmelsbach, F.; Kley, J.; Lehmann-Lintz, T., Alicyclic carboxylic acid

derivatives of benzomorphans and related scaffolds, medicaments containing such compounds and their use. 2009,

US Patent 0269791.

90 Aurrecoechea, J. M.; Gorgojo, J. M.; Saornil, C., J. Org. Chem. 2005, 70, 9640.

91 Bonjoch, J.; Solé, D.; García–Rubio, S.; Bosch, J., J. Am. Chem. Soc. 1997, 119, 7230.

92 Bosch, J.; Bonjoch, J.; Diez, A.; Linares, A.; Moral, M.; Rubiralta, M., Tetrahedron 1985, 41, 1753.

93 Diaba, F.; Bonjoch, J., Org. Biomol. Chem. 2009, 7, 2517.

94 Park, A.-Y.; Kim, W. H.; Kang, J.-A.; Lee, H. J.; Lee, C.-K.; Moon, H. R., Bioorg. & Med. Chem. 2011, 19, 3945.

95 Abdelkafi, H.; Evanno, L.; Deville, A.; Dubost, L.; Chiaroni, A.; Nay, B., Eur. J. Org. Chem. 2011, 15, 2789.

96 Knight, S. D.; Overman, L. E.; Pairaudeau, G., J. Am. Chem. Soc. 1993. 115, 9293.

97 (a) Fan, X.; Sans, V.; Yaseneva, P.; Plaza, D. D.; Williams, J.; Lapkin, A., Org. Process R&D 2012, 16, 1039; (b)

Takano, S.; Satoh, S.; Ogasawara, K., J. Chem. Soc., Chem Commun. 1988, 1, 59.

98 Shing, T. K. M.; Jiang, Q., J. Org. Chem. 2000, 65, 7059.

99 Ravindar, K.; Reddy, M. S.; Lindqvist, L.; Pelletier, J.; Deslongchamps, P., J. Org. Chem. 2011, 76, 1269.

100 Shimawaki, K.; Fujisawa, Y.; Sato, F.; Fujitani, N; Kurogochi, M.; Hoshi, H.; Hinou, H.; Nishamura, S.-I.,

Angew. Chem., Int. Ed. Engl. 2007, 46, 3074.

101 Kam, T. S.; Choo, Y. M., Phytochemistry 2004, 65, 603.

102 (a) Kam, T. S.; Iek, I.-H.; Choo, Y. M., Phytochemistry 1999, 51, 839; (b) Kam, T. S.; Choo, Y. M., J. Nat.

Products 2004, 67, 547.

103 Taskinen, E., J. Phys. Org. Chem. 2007, 20, 539.

104 Halcomb, R. L.; Boyer, S. H.; Wittman, M. D.; Olson, S. H.; Denhart, D. J.; Liu, K. K. C.; Danishefsky, S. J., J.

Am. Chem. Soc. 1995, 117, 5720.

105 Koci, J.; Grandclaude, V.; Massonneau, M.; Richard, J.-A.; Romieu, A.; Renard, P.-Y., Chem. Commun. 2011,

47, 6713.

References

257

106

Tang, Y.; Cole, K. P.; Buchanan, G. S.; Li, G.; Hsung, R. P., Org. Lett. 2009, 11, 1591.

107 For a review on the chemistry and synthetic applications of lactam-derived vinyl triflates and phosphates, see

Occhiato, E. G., Mini-Rev. Org. Chem. 2004, 1, 149.

108 Dolle, R. E.; Schmidt, S. J.; Erhard, K. F.; Kruse, L. I., J. Am. Chem. Soc. 1989, 11, 278.

109 Scott, W. J.; Stille, J. K., J. Am. Chem. Soc. 1986, 108, 3033.

110 Dolle, R. E.; Schmidt, S. J.; Erhard, K. F.; Kruse, L. I., J. Am. Chem. Soc. 1989, 11, 278.

111 Chen, Z.; Izenwasser, S.; Katz, J. L.; Zhu, N.; Klein, C. L.; Trudell, M. L., J. Med. Chem. 1996, 39, 4744.

112 Walker, T. L.; Malasi, W.; Bhide, S.; Parker, T.; Zhang, D.; Freedman, A.; Modarelli, J. M.; Engle, J.T.; Ziegler,

C. J., Custer, P.; Youngs, W. J.; Taschner, M. J., Tetrahedron Lett. 2012, 53, 6548.

113 Kneiss, T.; Laube, M.; Bergmann, R.; Sehn, F.; Graf.; Steinbach, J.; Wuest, F.; Pietzsch, J., Bioorg. & Med.

Chem. 2012, 20, 3410.

114 Ankner, T.; Hilmersson, G. R., Org. Lett. 2009, 11, 503.

115 (a) Nyasse, B.; Grehn, L.; Ragnarsson, U., Chem. Commun. 1997, 11, 1017; (b) Sridhar, M.; Kumar, B. A.;

Narender, R., Tetrahedron Lett. 1998, 39, 2847.

116 Youn, S. W.; Bihn, J. H.; Kim, B. S., Org. Lett. 2011, 13, 3738.

117 Mayerl, F.; Hesse, M., Helv. Chim. Acta 1978, 61, 337.

118 Wright, C. W.; Allen, D.; Cai, Y.; Phillipson, J. D.; Said, I. M.; Kirby, G. C.; Warhurst, D. C., Phytotheraphy

Research 1992, 6, 121.

119 Aggarwal, V. K.; Astle, C. J.; Rogers–Evans, M., Org. Lett. 2004, 6, 1469.

120 Davies, H. M. L.; Matasi, J.; Hodges, M.; Huby, N.; Thornley, C.; Kong, N.; Houser, J. J. Org. Chem. 1997, 62,

1095.

121 (a) Babinski, D.; Soltani, O.; Frantz, D. E., Org. Lett. 2008, 10, 2901; (b) Frantz, D. E.; Weaver, D. G.; Carey, J.

P.; Kress, M. H.; Dolling, U. H., Org. Lett. 2002, 4, 4717.

122 Craig, D.; Goldberg, F. W.; Pett, R. W.; Tholen, N. T. H.; White, A. P., Chem. Commun. 2013, 81, 9275.

123 Berry, M. B.; Craig, D., Synlett 1992, 1, 41.

124 Nemoto, T.; Yamamoto, N.; Wada, N.; Harada, Y.; Tomatsu, M.; Ishighara, M.; Hirayama, S.; Iwai, T.; Fujii, H.;

Nagase, H., Bioorg. & Med. Chem. Lett. 2013, 23, 268.

125 Royals, E. E.; Brannock, K. C., J. Am. Chem. Soc. 1954, 76, 3041.

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